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1
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Goldman JW, Bueno AM, Dooms C, Jhaveri K, de Miguel M, Piha-Paul SA, Unni N, Zick A, Mahipal A, Suga JM, Naltet C, Antoñanzas M, Crown J, Bebchuk J, Eli LD, Lowenthal BH, Mahalingam D. Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial. Clin Lung Cancer 2025; 26:191-200.e1. [PMID: 39828466 DOI: 10.1016/j.cllc.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/21/2024] [Accepted: 12/05/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3-5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. PATIENTS AND METHODS Eligible patients had ECOG performance status 0-2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. RESULTS Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5-37.5); ORR was 32.3% (95% CI: 16.7-51.4); median PFS 5.75 months (95% CI: 2.27-9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9-9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). CONCLUSION Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.
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Affiliation(s)
| | | | - Christophe Dooms
- University Hospitals Leuven, Respiratory Diseases, Leuven, Belgium
| | - Komal Jhaveri
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Nisha Unni
- The University of Texas Southwestern Medical Center, Dallas, TX
| | - Aviad Zick
- Hadassah Medical Center Hebrew University of Jerusalem, Oncology, Jerusalem, Israel
| | | | | | | | | | - John Crown
- St Vincent's University Hospital, Oncology, Dublin, Ireland
| | | | - Lisa D Eli
- Puma Biotechnology Inc., Los Angeles, CA
| | | | - Devalingam Mahalingam
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Medicine, Chicago, IL
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2
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Salbini M, Formato A, Mongiardi MP, Levi A, Falchetti ML. Kinase-Targeted Therapies for Glioblastoma. Int J Mol Sci 2025; 26:3737. [PMID: 40332381 PMCID: PMC12027600 DOI: 10.3390/ijms26083737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/08/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
Protein phosphorylation and dephosphorylation are key mechanisms that regulate cellular activities. The addition or removal of phosphate groups by specific enzymes, known as kinases and phosphatases, activates or inhibits many enzymes and receptors involved in various cell signaling pathways. Dysregulated activity of these enzymes is associated with various diseases, predominantly cancers. Synthetic and natural single- and multiple-kinase inhibitors are currently being used as targeted therapies for different tumors, including glioblastoma. Glioblastoma IDH-wild-type is the most aggressive brain tumor in adults, with a median overall survival of 15 months. The great majority of glioblastoma patients present mutations in receptor tyrosine kinase (RTK) signaling pathways responsible for tumor initiation and/or progression. Despite this, the multi-kinase inhibitor regorafenib has only recently been approved for glioblastoma patients in some countries. In this review, we analyze the history of kinase inhibitor drugs in glioblastoma therapy.
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Affiliation(s)
| | | | | | | | - Maria Laura Falchetti
- Institute of Biochemistry and Cell Biology, National Research Council, Via Ercole Ramarini 32, Monterotondo, 00015 Rome, Italy; (M.S.); (A.F.); (M.P.M.); (A.L.)
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3
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Kim J, Park S, Ku BM, Ahn MJ. Updates on the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer. Cancer 2025; 131 Suppl 1:e35778. [PMID: 40171939 DOI: 10.1002/cncr.35778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/28/2024] [Accepted: 09/30/2024] [Indexed: 04/04/2025]
Abstract
This review provides a comprehensive update on the evolving landscape of treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, particularly focusing on advances in precision medicine and overcoming acquired resistance. Initial success with first-generation EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC has paved the way for precision oncology and subsequent development of third-generation EGFR TKIs, the current standard of care as first-line therapy in advanced stage NSCLC. Furthermore, a combinational approach of third-generation EGFR TKI with chemotherapy or amivantamab was associated with prolonged progression-free survival. The role of EGFR TKIs also has been investigated in locally advanced and early stage NSCLC, including perioperative and neoadjuvant settings. However, most patients experience acquired resistance, and the resistance mechanism is quite complex and heterogeneous, highlighting the importance of tailored subsequent therapeutic approaches. Overall, this review underscores the dynamic landscape of EGFR-mutated NSCLC treatment, emphasizing the need for personalized strategies to optimize patient outcomes.
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Affiliation(s)
- Jinyong Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Sehhoon Park
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Bo Mi Ku
- Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Myung-Ju Ahn
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
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Abdo EL, Ajib I, El Mounzer J, Husseini M, Kalaoun G, Matta TM, Mosleh R, Nasr F, Richani N, Khalil A, Shayya A, Ghanem H, Faour WH. Molecular biology of the novel anticancer medications: a focus on kinases inhibitors, biologics and CAR T-cell therapy. Inflamm Res 2025; 74:41. [PMID: 39960501 DOI: 10.1007/s00011-025-02008-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 05/09/2025] Open
Abstract
INTRODUCTION Cancer treatment underwent significant changes in the last few years with the introduction of novel treatments targeting the immune system. OBJECTIVES The objective of this review is to discuss novel anticancer drugs including kinase inhibitors, biologics and cellular therapy with CAR-T cells. METHODS Most recent research articles were extracted from PubMed using keywords such as "kinases inhibitors", "CAR-T cell therapy". RESULTS AND DISCUSSION The number of kinase inhibitors is significantly increasing due to their demonstrated effectiveness in combination with biologics. CAR-T represented a major breakthrough in the field. Also, it focused on their mechanisms of action and the rational of their use either alone or in combination in relation to their modes of action.
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Affiliation(s)
- Elia-Luna Abdo
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Imad Ajib
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Jason El Mounzer
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Mohammad Husseini
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Gharam Kalaoun
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Tatiana-Maria Matta
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Reine Mosleh
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Fidel Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Nour Richani
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
| | - Anwar Shayya
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Hady Ghanem
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon
- Department of Hematology-Oncology, Lebanese American University Medical Center- Rizk Hospital, Beirut, Lebanon
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Room 4722, P.O. Box 36, Byblos, Lebanon.
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Qian JY, Lou CY, Chen YL, Ma LF, Hou W, Zhan ZJ. A prospective therapeutic strategy: GPX4-targeted ferroptosis mediators. Eur J Med Chem 2025; 281:117015. [PMID: 39486214 DOI: 10.1016/j.ejmech.2024.117015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/27/2024] [Accepted: 10/28/2024] [Indexed: 11/04/2024]
Abstract
As a crucial regulator of oxidative homeostasis, seleno-protein glutathione peroxidase 4 (GPX4) represents the primary defense system against ferroptosis, making it a promising target with important clinical application prospects. From the discovery of covalent and allosteric sites in GPX4, substantial advancements in GPX4-targeted small molecules have been made through diverse discovery and design strategies in recent years. Moreover, as an emerging hotspot in drug development, seleno-organic compounds can functionally mimic GPX4 to reduce hydroperoxides. To facilitate the further development of selective ferroptosis mediators as potential pharmaceutical agents, this review comprehensively covers all GPX4-targeted small molecules, including inhibitors, degraders, and activators. In addition, seleno-organic compounds as GPX mimics are also included. We also provide perspectives regarding challenges and future research directions in this field.
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Affiliation(s)
- Jia-Yu Qian
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Chao-Yuan Lou
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Yi-Li Chen
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Lie-Feng Ma
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Wei Hou
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
| | - Zha-Jun Zhan
- Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China.
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6
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Li Y, Li G, Zheng Z, Wen W, Zhao H, Liu X, Xie J, Han L. Benefits of osimertinib treat a lung adenocarcinoma patient with germline EGFR T790M, somatic EGFR 19-Del, TP53 and PIK3CA mutations. Hered Cancer Clin Pract 2024; 22:13. [PMID: 39160638 PMCID: PMC11331667 DOI: 10.1186/s13053-024-00286-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/06/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Somatic mutations in the EGFR gene occur in about 50% of non-small cell lung cancers, with the T790M mutation significantly contributing to secondary resistance against EGFR-TKI drugs. However, EGFR T790M germline mutations rarely occur. CASE PRESENTATION In this study, we report a case of a lung adenocarcinoma family lineage linked to a germline EGFR T790M mutation. The main subject was diagnosed with stage IV lung adenocarcinoma and experienced a 19-month period without disease progression while treated with Osimertinib. We collected both clinicopathological and familial data from a patient with lung adenocarcinoma. Next-generation sequencing of 40 key genes was performed on the proband's tumor tissue. To detect EGFR germline mutations, Sanger sequencing was conducted on peripheral blood mononuclear cells from the proband and his two daughters. Mutations such as EGFR T790M, EGFR 19-Del, TP53, and PIK3CA were identified in the proband's lung cancer tissue. Additionally, germline EGFR T790M mutations were confirmed in the proband and his daughters through sequencing of their peripheral blood samples. CT scans revealed multiple pulmonary nodules in both daughters. CONCLUSIONS These observations suggest that germline mutations in EGFR T790M could be strongly linked to a familial predisposition to lung cancer.
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Affiliation(s)
- Yingxue Li
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China
- Department of Pathology, School of Basic Medicine Science, Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Guangqi Li
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, People's Republic of China
| | - Zheng Zheng
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China
| | - Wenjuan Wen
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China
| | - Haihui Zhao
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China
| | - Xia Liu
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China
| | - Jiaping Xie
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China.
- Department of Gastroenterology, The Fifth People's Hospital of Liaocheng, Liaocheng, 252000, Shandong, People's Republic of China.
| | - Lin Han
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong, People's Republic of China.
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7
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Wang X, DeFilippis RA, Yan W, Shah NP, Li HY. Overcoming Secondary Mutations of Type II Kinase Inhibitors. J Med Chem 2024; 67:9776-9788. [PMID: 38837951 PMCID: PMC11586107 DOI: 10.1021/acs.jmedchem.3c01629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.
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Affiliation(s)
- Xiuqi Wang
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States
| | - Rosa Anna DeFilippis
- Division of Hematology/Oncology, University of California, San Francisco, California 94143, United States
| | - Wei Yan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States
- Department of Pharmacology, School of Medicine, The University of Texas Health San Antonio, San Antonio, Texas 78229, United States
| | - Neil P Shah
- Division of Hematology/Oncology, University of California, San Francisco, California 94143, United States
| | - Hong-Yu Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States
- Department of Pharmacology, School of Medicine, The University of Texas Health San Antonio, San Antonio, Texas 78229, United States
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8
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Eissa IH, G Yousef R, Elkady H, Alsfouk AA, Husein DZ, Ibrahim IM, El-Deeb N, Kenawy AM, Eldehna WM, Elkaeed EB, Metwaly AM. New apoptotic anti-triple-negative breast cancer theobromine derivative inhibiting EGFRWT and EGFR T790M: in silico and in vitro evaluation. Mol Divers 2024; 28:1153-1173. [PMID: 37162644 DOI: 10.1007/s11030-023-10644-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 03/29/2023] [Indexed: 05/11/2023]
Abstract
A new theobromine-derived EGFR inhibitor (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(2,6-dimethylphenyl)acetamide) has been developed that has the essential structural characteristics to interact with EGFR's pocket. The designed compound is 2,6-di ortho methylphenyl)acetamide derivative of the well-known alkaloid, theobromine, (T-1-DOMPA). Firstly, deep DFT studies have been conducted to study the optimized chemical structure, molecular orbital and chemical reactivity analysis of T-1-DOMPA. Then, T-1-DOMPA's anticancer potentialities were estimated first through a structure-based computational approach. Utilizing molecular docking, molecular dynamics, MD, simulations over 100 ns, MM-PBSA and PLIP studies, T-1-DOMPA bonded to and inhibited the EGFR protein effectively. Subsequently, the ADMET profiles of T-1-DOMPA were computed before preparation, and its drug-likeness was anticipated. Therefore, T-1-DOMPA was prepared for the purposes of scrutinizing both the design and the results obtained in silico. The in vitro potential of T-1-DOMPA against triple-negative breast cancer cell lines, MDA- MB-231, was very promising with an IC50 value of1.8 µM, comparable to the reference drug (0.9 µM), and a much higher selectivity index of 2.6. Interestingly, T-1-DOMPA inhibited three other cancer cell lines (CaCO-2, HepG-2, and A549) with IC50 values of 1.98, 2.53, and 2.39 µM exhibiting selectivity index values of 2,4, 1.9, and 2, respectively. Additionally, T-1-DOMPA prevented effectively the MDA-MB-231cell line's healing and migration abilities. Also, T-1-DOMPA's abilities to induce apoptosis were confirmed by acridine orange/ethidium bromide (AO/EB) staining assay. Finally, T-1-DOMPA caused an up-regulation of the gene expression of the apoptotic gene, Caspase-3, in the treated MDA-MB-231cell.
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Affiliation(s)
- Ibrahim H Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
| | - Reda G Yousef
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt
| | - Hazem Elkady
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt
| | - Aisha A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia
| | - Dalal Z Husein
- Chemistry Department, Faculty of Science, New Valley University, El-Kharja, 72511, Egypt
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Cairo, 12613, Egypt
| | - Nehal El-Deeb
- Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria, Egypt
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications (SRTA City), New Borg El-Arab City, 21934, Alexandria, Egypt
| | - Ahmed M Kenawy
- Nucleic Acids Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, 21934, Alexandria, Egypt
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
- School of Biotechnology, Badr University in Cairo, Badr City, 11829, Egypt
| | - Eslam B Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi Arabia
| | - Ahmed M Metwaly
- Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria, Egypt.
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
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9
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Du S, Hu X, Menéndez-Arias L, Zhan P, Liu X. Target-based drug design strategies to overcome resistance to antiviral agents: opportunities and challenges. Drug Resist Updat 2024; 73:101053. [PMID: 38301487 DOI: 10.1016/j.drup.2024.101053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/22/2023] [Accepted: 01/09/2024] [Indexed: 02/03/2024]
Abstract
Viral infections have a major impact in human health. Ongoing viral transmission and escalating selective pressure have the potential to favor the emergence of vaccine- and antiviral drug-resistant viruses. Target-based approaches for the design of antiviral drugs can play a pivotal role in combating drug-resistant challenges. Drug design computational tools facilitate the discovery of novel drugs. This review provides a comprehensive overview of current drug design strategies employed in the field of antiviral drug resistance, illustrated through the description of a series of successful applications. These strategies include technologies that enhance compound-target affinity while minimizing interactions with mutated binding pockets. Furthermore, emerging approaches such as virtual screening, targeted protein/RNA degradation, and resistance analysis during drug design have been harnessed to curtail the emergence of drug resistance. Additionally, host targeting antiviral drugs offer a promising avenue for circumventing viral mutation. The widespread adoption of these refined drug design strategies will effectively address the prevailing challenge posed by antiviral drug resistance.
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Affiliation(s)
- Shaoqing Du
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China
| | - Xueping Hu
- Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao 266237, PR China
| | - Luis Menéndez-Arias
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain.
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
| | - Xinyong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
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10
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Ahmad Ansari I, Debnath B, Kar S, Patel HM, Debnath S, Zaki MEA, Pal P. Identification of potential edible spices as EGFR and EGFR mutant T790M/L858R inhibitors by structure-based virtual screening and molecular dynamics. J Biomol Struct Dyn 2024; 42:2464-2481. [PMID: 37349948 DOI: 10.1080/07391102.2023.2223661] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 04/14/2023] [Indexed: 06/24/2023]
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinases are overexpressed in several human cancers and could serve as a promising anti-cancer drug target. With this in view, the main aim of the present study was to identify spices having the potential to inhibit EGFR tyrosine kinase. The structure-based virtual screening of spice database consisting of 1439 compounds with EGFR tyrosine kinase (PDB ID: 3W32) was carried out using Glide. Top scored 18 hits (XP Glide Score ≥ -10.0 kcal/mol) was further docked with three EGFR tyrosine kinases and three EGFR T790M/L858R mutants using AutodockVina, followed by ADME filtration. The best three hits were further refined by Molecular Dynamics (MD) simulation and MM-GBSA-based binding energy calculation. The overall docking results of the selected hits with both EGFR and EGFR T790M/L858R were quite satisfactory and showed strong binding compared to the three coligands. Detailed MD analysis of CL_07, AC_11 and AS_49 also showed the stability of the protein-ligand complexes. Moreover, the hits were drug-like, and MM-GBSA binding free energy of CL_07 and AS_49 was established to be far better. AC_11 was found to be similar to the known inhibitor Gefitinib. Most of the potential hits are available in Allium cepa, CL_07 and AS_49 available in Curcuma longa and Allium sativum, respectively. Therefore, these three spices could be used as a potential therapeutic candidate against cancer caused by overexpression of EGFR after validation of the observations of this study in in-vitro experiments. Further extensive work is needed to improve the scaffolds CL_07, AC_11, AC_17, and AS_49 as potential anti-cancer drugs.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Iqrar Ahmad Ansari
- Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule, Maharashtra, India
- Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule), Maharashtra, India
| | - Bimal Debnath
- Department of Forestry and Biodiversity, Tripura University, Suryamaninagar, Tripura, India
| | - Saikat Kar
- Department of Obstetrics and Gynecology, Agartala Govt. Medical College, Tripura, India
| | - Harun M Patel
- Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule), Maharashtra, India
| | - Sudhan Debnath
- Department of Chemistry, Netaji Subhas Mahavidyalaya, Udaipur, Tripura, India
| | - Magdi E A Zaki
- Department of Chemistry, Imam Mohammad Ibn Saud Islamic University, Faculty of Science, Riyadh, Saudi Arabia
| | - Pinaki Pal
- Department of Physics, RamkrishnaMahavidyalay, Unokoti, Tripura, India
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11
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Sobh EA, Dahab MA, Elkaeed EB, Alsfouk AA, Ibrahim IM, Metwaly AM, Eissa IH. Computer aided drug discovery (CADD) of a thieno[2,3- d]pyrimidine derivative as a new EGFR inhibitor targeting the ribose pocket. J Biomol Struct Dyn 2024; 42:2369-2391. [PMID: 37129193 DOI: 10.1080/07391102.2023.2204500] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 04/14/2023] [Indexed: 05/03/2023]
Abstract
Depending on the pharmacophoric characteristics of EGFR inhibitors, a new thieno[2,3-d]pyrimidine derivative has been developed. Firstly, the potential inhibitory effect of the designed compound against EGFR has been proven by docking experiments that showed correct binding modes and excellent binding energies of -98.44 and -88.00 kcal/mol, against EGFR wild-type and mutant type, respectively. Furthermore, MD simulations studies confirmed the precise energetic, conformational, and dynamic alterations that occurred after binding to EGFR. The correct binding was also confirmed by essential dynamics studies. To further investigate the general drug-like properties of the developed candidate, in silico ADME and toxicity studies have also been carried out. The thieno[2,3-d]pyrimidine derivative was synthesized following the earlier promising findings. Fascinatingly, the synthesized compound (4) showed promising inhibitory effects against EGFRWT and EGFRT790M with IC50 values of 25.8 and 182.3 nM, respectively. Also, it exhibited anticancer potentialities against A549 and MCF-7cell lines with IC50 values of 13.06 and 20.13 µM, respectively. Interestingly, these strong activities were combined with selectivity indices of 2.8 and 1.8 against the two cancer cell lines, respectively. Further investigations indicated the ability of compound 4 to arrest the cancer cells' growth at the G2/M phase and to increase early and late apoptosis percentages from 2.52% and 2.80 to 17.99% and 16.72%, respectively. Additionally, it was observed that compound 4 markedly increased the levels of caspase-3 and caspase-9 by 4 and 3-fold compared to the control cells. Moreover, it up-regulated the level of BAX by 3-fold and down-regulated the level of Bcl-2 by 3-fold affording a BAX/Bcl-2 ratio of 9.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Eman A Sobh
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Shibin-Elkom, Menoufia, Egypt
| | - Mohammed A Dahab
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Eslam B Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Aisha A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Ahmed M Metwaly
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
- Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt
| | - Ibrahim H Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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12
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Li Y, Yang Y, Zhong C, Xiao D, Zhou C. Highly Sensitive Detection of T790 M with a Three-Level Characteristic Current by Thymine-Hg(II)-Thymine in the α-Hemolysin Nanopore. Anal Chem 2024; 96:3587-3592. [PMID: 38372205 DOI: 10.1021/acs.analchem.3c05571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Sensitive detection of resistance mutation T790 M is of great significance for early diagnosis and prognostic monitoring of non-small-cell lung cancer (NSCLC). In this paper, we showed a highly sensitive detection strategy for T790 M using a three-level characteristic current signal pattern in an α-hemolysin nanopore. A probe was designed that formed a C-T mismatched base pair with wild-type/P and a T-T mismatched with the T790M/P. The T790M/P produced a unique three-level characteristic current signal in the presence of mercury ions(II): first, T790M-Hg2+-P entering the vestibule of α-HL under the transmembrane potential and overhang of probe occupying the β-barrel, then probe unzipping from the T790M/P, T790 M temporally residing inside the nanocavity due to the interaction with Hg(II), and finally T790 M passing through the β-barrel. The blocking current distribution was concentrated with a small relative standard deviation of about 3%, and the signal peaks of T790 M and wild-type can be completely separated with a high separation resolution of more than 2.5, which achieved the highly sensitive detection of T790 M down to 0.001 pM (confidence level P 95%) with a linear range from 0.001 pM to 1 nM in human serum samples. This highly sensitive recognition strategy enables the detection of low abundance T790 M and provides a method for prognostic monitoring in NSCLC patients.
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Affiliation(s)
- Yaping Li
- College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
| | - Yongqi Yang
- College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
| | - Chunmeng Zhong
- College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
| | - Dan Xiao
- College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
| | - Cuisong Zhou
- College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
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13
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Vaishnavi A, Kinsey CG, McMahon M. Preclinical Modeling of Pathway-Targeted Therapy of Human Lung Cancer in the Mouse. Cold Spring Harb Perspect Med 2024; 14:a041385. [PMID: 37788883 PMCID: PMC10760064 DOI: 10.1101/cshperspect.a041385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Animal models, particularly genetically engineered mouse models (GEMMs), continue to have a transformative impact on our understanding of the initiation and progression of hematological malignancies and solid tumors. Furthermore, GEMMs have been employed in the design and optimization of potent anticancer therapies. Increasingly, drug responses are assessed in mouse models either prior, or in parallel, to the implementation of precision medical oncology, in which groups of patients with genetically stratified cancers are treated with drugs that target the relevant oncoprotein such that mechanisms of drug sensitivity or resistance may be identified. Subsequently, this has led to the design and preclinical testing of combination therapies designed to forestall the onset of drug resistance. Indeed, mouse models of human lung cancer represent a paradigm for how a wide variety of GEMMs, driven by a variety of oncogenic drivers, have been generated to study initiation, progression, and maintenance of this disease as well as response to drugs. These studies have now expanded beyond targeted therapy to include immunotherapy. We highlight key aspects of the relationship between mouse models and the evolution of therapeutic approaches, including oncogene-targeted therapies, immunotherapies, acquired drug resistance, and ways in which successful antitumor strategies improve on efficiently translating preclinical approaches into successful antitumor strategies in patients.
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Affiliation(s)
- Aria Vaishnavi
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA
| | - Conan G Kinsey
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84112, USA
| | - Martin McMahon
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA
- Department of Dermatology, University of Utah, Salt Lake City, Utah 84112, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA
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14
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Qu Z, Krabill AD, Zhang ZY. High-Throughput Discovery and Characterization of Covalent Inhibitors for Protein Tyrosine Phosphatases. Methods Mol Biol 2024; 2743:301-316. [PMID: 38147223 DOI: 10.1007/978-1-0716-3569-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Covalent inhibition has gained increasing interest in targeting the undruggable protein tyrosine phosphatases (PTPs). However, a systematic method for discovering and characterizing covalent PTP inhibitors has yet to be established. Here, we describe a workflow involving high-throughput screening of covalent fragment libraries and a novel biochemical assay that enables the acquisition of kinetics parameters of PTP inhibition by covalent inhibitors with higher throughput.
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Affiliation(s)
- Zihan Qu
- Department of Chemistry, Purdue University, West Lafayette, IN, USA
| | - Aaron D Krabill
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
| | - Zhong-Yin Zhang
- Department of Chemistry, Purdue University, West Lafayette, IN, USA.
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
- Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
- Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.
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15
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Goullieux M, Zoete V, Röhrig UF. Two-Step Covalent Docking with Attracting Cavities. J Chem Inf Model 2023; 63:7847-7859. [PMID: 38049143 PMCID: PMC10751798 DOI: 10.1021/acs.jcim.3c01055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 12/06/2023]
Abstract
Due to their various advantages, interest in the development of covalent drugs has been renewed in the past few years. It is therefore important to accurately describe and predict their interactions with biological targets by computer-aided drug design tools such as docking algorithms. Here, we report a covalent docking procedure for our in-house docking code Attracting Cavities (AC), which mimics the two-step mechanism of covalent ligand binding. Ligand binding to the protein cavity is driven by nonbonded interactions, followed by the formation of a covalent bond between the ligand and the protein through a chemical reaction. To test the performance of this method, we developed a diverse, high-quality, openly accessible re-docking benchmark set of 95 covalent complexes bound by 8 chemical reactions to 5 different reactive amino acids. Combination with structures from previous studies resulted in a set of 304 complexes, on which AC obtained a success rate (rmsd ≤ 2 Å) of 78%, outperforming two state-of-the-art covalent docking codes, genetic optimization for ligand docking (GOLD (66%)) and AutoDock (AD (35%)). Using a more stringent success criterion (rmsd ≤ 1.5 Å), AC reached a success rate of 71 vs 55% for GOLD and 26% for AD. We additionally assessed the cross-docking performance of AC on a set of 76 covalent complexes of the SARS-CoV-2 main protease. On this challenging test set of mainly small and highly solvent-exposed ligands, AC yielded success rates of 58 and 28% for re-docking and cross-docking, respectively, compared to 45 and 17% for GOLD.
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Affiliation(s)
- Mathilde Goullieux
- SIB
Swiss Institute of Bioinformatics, Molecular Modeling Group, CH-1015 Lausanne, Switzerland
| | - Vincent Zoete
- SIB
Swiss Institute of Bioinformatics, Molecular Modeling Group, CH-1015 Lausanne, Switzerland
- Department
of Oncology UNIL-CHUV, Lausanne University, Ludwig Institute for Cancer Research
Lausanne Branch, CH-1066 Epalinges, Switzerland
| | - Ute F. Röhrig
- SIB
Swiss Institute of Bioinformatics, Molecular Modeling Group, CH-1015 Lausanne, Switzerland
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16
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Bhanja KK, Sharma M, Patra N. Uncovering the Structural and Binding Insights of Dual Inhibitors Simultaneously Targeting Two Distinct Sites on EGFR Kinase. J Phys Chem B 2023; 127:10749-10765. [PMID: 38055900 DOI: 10.1021/acs.jpcb.3c04337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023]
Abstract
Epidermal growth factor receptor (EGFR) is the first growth factor receptor identified in normal cells that is related to the receptor tyrosine kinase, which causes regular cell division. A point mutation in EGFR intracellular kinase domain forces the abnormal cell divisions throughout time, leading to non-small cell lung cancer (NSCLC) transformation. Thus, competitive inhibitors that bind to the ATP binding pocket have been developed as a targeted therapy for NSCLC. The third-generation kinase inhibitor Osimertinib is currently playing a very vital role in the treatment of NSCLC. However, it is not effective toward the C797S kinase domain mutation. For this reason, fourth-generation kinase noncompetitive inhibitors are introduced which work through binding to an allosteric pocket near the ATP binding region and act as a better binding agent for this mutated kinase domain. However, the problem is that these single fourth-generation kinase inhibitors may not be as effective as a single agent. The aim of this work was to apply combinations of these two inhibitors together in different binding regions of EGFR without overlapping the resistance mechanism to obtain the key direct and indirect interactions occurring between them. Moreover, the free energy of dissociation of an inhibitor from its binding sites in the presence of a second inhibitor immobilized in another binding site was also the focus of the study. To realize this aim, we performed conventional molecular dynamics simulations and principal component analysis and dynamic cross-correlation matrices along with umbrella sampling. Our results demonstrated that binding of dual inhibitors triggered conformational changes of the protein more toward the inactive state. Furthermore, allosteric inhibitors bound more strongly to protein kinase EGFR than the orthosteric inhibitors in the presence of dual inhibitors. Finally, the binding mechanism and important hydrogen-bonding residues during unbinding of the inhibitors were fully elucidated. This study provides insight into the binding of the receptor-orthosteric inhibitor-allosteric inhibitor, which can be helpful for further design of novel inhibitors that have a better inhibitory action.
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Affiliation(s)
- Kousik K Bhanja
- Department of Chemistry & Chemical Biology, Indian Institute of Technology (ISM) Dhanbad, Dhanbad 826004, India
| | - Madhur Sharma
- Department of Chemistry & Chemical Biology, Indian Institute of Technology (ISM) Dhanbad, Dhanbad 826004, India
| | - Niladri Patra
- Department of Chemistry & Chemical Biology, Indian Institute of Technology (ISM) Dhanbad, Dhanbad 826004, India
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17
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El-Dash Y, Khalil NA, Ahmed EM, Hassanin SO, Gowifel AMH, Hassan MSA. Synthesis of novel nicotinic acid derivatives of potential antioxidant and anticancer activity. Arch Pharm (Weinheim) 2023; 356:e2300250. [PMID: 37792247 DOI: 10.1002/ardp.202300250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 09/10/2023] [Accepted: 09/13/2023] [Indexed: 10/05/2023]
Abstract
This study comprises the design and synthesis of novel nicotinic acid-based cytotoxic agents with selective inhibitory efficacy against the vascular endothelial growth factor receptor-2 (VEGFR-2). Screening of novel compounds for cytotoxicity was assessed against 60 human cancer cell lines. The two most active compounds, 5b and 5c, and the reference drugs sorafenib and doxorubicin were investigated against HCT-15, PC-3, and CF-295 cancer cell lines. Compound 5c exhibited the highest cytotoxic potential compared to doxorubicin against the HCT-15 and PC-3 tumor cell lines. Moreover, it exhibited higher cytotoxic potential and selectivity toward the HCT-15 cell panel compared with sorafenib. Compound 5c demonstrated promising VEGFR-2 inhibition (concentration needed to inhibit cell viability by 50%, IC50 = 0.068 μM) and superior VEGFR-2 selectivity over the epidermal growth factor receptor and platelet-derived growth factor receptor-β enzymes. It also reduced the total and phosphorylated VEGFR-2 and induced apoptosis, as evidenced by a 4.3-fold rise in caspase-3 levels. The antioxidant potential of the new compounds was determined via measuring the superoxide dismutase (SOD) levels, among which compound 5c exhibited an SOD level almost comparable to ascorbic acid. These results suggested that compound 5c exhibited dual cytotoxic and antioxidant activities. Docking of 5c into the VEGFR-2 pocket showed a similar binding mode to sorafenib. Moreover, the ADME (absorption, distribution, metabolism, and excretion) profile of 5c outlined drug-likeness. Finally, The density functional theory calculations displayed an increased binding affinity of 5c to the target enzyme.
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Affiliation(s)
- Yara El-Dash
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nadia A Khalil
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Eman M Ahmed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Soha O Hassanin
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, Egypt
| | - Ayah M H Gowifel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, Egypt
| | - Marwa S A Hassan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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18
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Rodriguez SMB, Kamel A, Ciubotaru GV, Onose G, Sevastre AS, Sfredel V, Danoiu S, Dricu A, Tataranu LG. An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma. Int J Mol Sci 2023; 24:11110. [PMID: 37446288 DOI: 10.3390/ijms241311110] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood-brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents.
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Affiliation(s)
- Silvia Mara Baez Rodriguez
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", Soseaua Berceni 12, 041915 Bucharest, Romania
| | - Amira Kamel
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", Soseaua Berceni 12, 041915 Bucharest, Romania
| | - Gheorghe Vasile Ciubotaru
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", Soseaua Berceni 12, 041915 Bucharest, Romania
| | - Gelu Onose
- Neuromuscular Rehabilitation Department, Clinical Emergency Hospital "Bagdasar-Arseni", Soseaua Berceni 12, 041915 Bucharest, Romania
| | - Ani-Simona Sevastre
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 710204 Craiova, Romania
| | - Veronica Sfredel
- Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 710204 Craiova, Romania
| | - Suzana Danoiu
- Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 710204 Craiova, Romania
| | - Anica Dricu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 710204 Craiova, Romania
| | - Ligia Gabriela Tataranu
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", Soseaua Berceni 12, 041915 Bucharest, Romania
- Department of Neurosurgery, Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", 020022 Bucharest, Romania
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19
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Todsaporn D, Zubenko A, Kartsev V, Aiebchun T, Mahalapbutr P, Petrou A, Geronikaki A, Divaeva L, Chekrisheva V, Yildiz I, Choowongkomon K, Rungrotmongkol T. Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study. Molecules 2023; 28:molecules28073014. [PMID: 37049777 PMCID: PMC10096398 DOI: 10.3390/molecules28073014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/25/2023] [Accepted: 03/26/2023] [Indexed: 03/30/2023] Open
Abstract
Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end, a series of furopyridine derivatives were evaluated for their EGFR-based inhibition and antiproliferative activities using computational and biological approaches. We found that several compounds derived from virtual screening based on a molecular docking and solvated interaction energy (SIE) method showed the potential to suppress wild-type and mutant EGFR. The most promising PD13 displayed strong inhibitory activity against wild-type (IC50 of 11.64 ± 1.30 nM), L858R/T790M (IC50 of 10.51 ± 0.71 nM), which are more significant than known drugs. In addition, PD13 revealed a potent cytotoxic effect on A549 and H1975 cell lines with IC50 values of 18.09 ± 1.57 and 33.87 ± 0.86 µM, respectively. The 500-ns MD simulations indicated that PD13 formed a hydrogen bond with Met793 at the hinge region, thus creating excellent EGFR inhibitory activity. Moreover, the binding of PD13 in the hinge region of EGFR was the major determining factor in stabilizing the interactions via hydrogen bonds and van der Waals (vdW). Altogether, PD13 is a promising novel EGFR inhibitor that could be further clinically developed as fourth-generation EGFR-TKIs.
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20
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Sattler M, Mambetsariev I, Fricke J, Tan T, Liu S, Vaidehi N, Pisick E, Mirzapoiazova T, Rock AG, Merla A, Sharma S, Salgia R. A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine. J Clin Med 2023; 12:jcm12051936. [PMID: 36902723 PMCID: PMC10003860 DOI: 10.3390/jcm12051936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/22/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
The development of EGFR small-molecule inhibitors has provided significant benefit for the affected patient population. Unfortunately, current inhibitors are no curative therapy, and their development has been driven by on-target mutations that interfere with binding and thus inhibitory activity. Genomic studies have revealed that, in addition to these on-target mutations, there are also multiple off-target mechanisms of EGFR inhibitor resistance and novel therapeutics that can overcome these challenges are sought. Resistance to competitive 1st-generation and covalent 2nd- and 3rd-generation EGFR inhibitors is overall more complex than initially thought, and novel 4th-generation allosteric inhibitors are expected to suffer from a similar fate. Additional nongenetic mechanisms of resistance are significant and can include up to 50% of the escape pathways. These potential targets have gained recent interest and are usually not part of cancer panels that look for alterations in resistant patient specimen. We discuss the duality between genetic and nongenetic EGFR inhibitor drug resistance and summarize current team medicine approaches, wherein clinical developments, hand in hand with drug development research, drive potential opportunities for combination therapy.
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Affiliation(s)
- Martin Sattler
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Correspondence:
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Jeremy Fricke
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Tingting Tan
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Sariah Liu
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Nagarajan Vaidehi
- Department of Computational and Quantitative Medicine, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Evan Pisick
- City of Hope Chicago, 2520 Elisha Avenue, Zion, IL 60099, USA
| | - Tamara Mirzapoiazova
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Adam G. Rock
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Amartej Merla
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
| | - Sunil Sharma
- Division of Applied Cancer Research and Drug Discovery, Translational Genomic Research Institute (Tgen), 445 N 5th St, Phoenix, AZ 85004, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
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21
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Li T, Feng R, Chen B, Zhou J. EREG is a risk factor for the prognosis of patients with cervical cancer. Front Med (Lausanne) 2023; 10:1161835. [PMID: 37020674 PMCID: PMC10067667 DOI: 10.3389/fmed.2023.1161835] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Background Cervical cancer continues to threaten women's health worldwide. Identifying critical oncogenic molecules is important to drug development and prognosis prediction for patients with cervical cancer. Recent studies have demonstrated that epiregulin (EREG) is upregulated in various cancer types, which contributes to cancer progression by triggering the EGFR signaling pathway. However, the role of EREG is still unclear. Methods In this study, we first conducted a comprehensive biological analysis to investigate the expression of EREG in cervical cancer. Then, we investigated the correlations between EREG expression level and clinicopathological features. In addition, we validated the effects of EREG expression on the proliferation and apoptosis of cervical cancer cells. Results Based on the public database, we found that the expression of EREG was higher in advanced cervical cancer samples. Survival analysis showed that EREG was a risk factor for the prognosis of cervical cancer. In vitro experiments demonstrated that EREG knockdown undermined proliferation and promoted apoptosis in cancer cells. Conclusion EREG plays a vital role in the progression of cervical cancer, which contributes to hyperactive cell proliferation and decreased cell apoptosis. It might be a valuable target for prognosis prediction and drug development for cervical cancer in the future.
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Affiliation(s)
- Tianye Li
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ruijing Feng
- Department of Obstetrics and Gynecology, The Central Hospital of Wuhan, Wuhan, China
| | - Bingxin Chen
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianwei Zhou
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Jianwei Zhou
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22
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Elzahabi HSA, Nossier ES, Alasfoury RA, El-Manawaty M, Sayed SM, Elkaeed EB, Metwaly AM, Hagras M, Eissa IH. Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers. J Enzyme Inhib Med Chem 2022; 37:1053-1076. [PMID: 35821615 PMCID: PMC9291687 DOI: 10.1080/14756366.2022.2062752] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.
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Affiliation(s)
- Heba S A Elzahabi
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Eman S Nossier
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Rania A Alasfoury
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - May El-Manawaty
- Pharmacognosy Department, National Research Centre, Dokki, Cairo, Egypt
| | - Sara M Sayed
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Eslam B Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Ahmed M Metwaly
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.,Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt
| | - Mohamed Hagras
- Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Ibrahim H Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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Sonousi A, Hassan RA, Osman EO, Abdou AM, Emam SH. Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity. J Enzyme Inhib Med Chem 2022; 37:2644-2659. [PMID: 36146940 PMCID: PMC9518264 DOI: 10.1080/14756366.2022.2118735] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Nineteen new quinazolin-4(3H)-one derivatives 3a–g and 6a–l were designed and synthesised to inhibit EGFR. The antiproliferative activity of the synthesised compounds was tested in vitro against 60 different human cell lines. The most potent compound 6d displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460 with GI50 = 0.789 µM. It also showed potent cytostatic activity against 40 different cancer cell lines (TGI range: 2.59–9.55 µM). Compound 6d potently inhibited EGFR with IC50 = 0.069 ± 0.004 µM in comparison to erlotinib with IC50 value of 0.045 ± 0.003 µM. Compound 6d showed 16.74-fold increase in total apoptosis and caused cell cycle arrest at G1/S phase in breast cancer HS 578T cell line. Moreover, the most potent derivatives were docked into the EGFR active site to determine their binding mode and confirm their ability to satisfy the pharmacophoric features required for EGFR inhibition.
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Affiliation(s)
- Amr Sonousi
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Rasha A Hassan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Eman O Osman
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Amr M Abdou
- Department of Microbiology and Immunology, National Research Centre, Dokki, Giza, Egypt
| | - Soha H Emam
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Lu D, Yu X, Lin H, Cheng R, Monroy EY, Qi X, Wang MC, Wang J. Applications of covalent chemistry in targeted protein degradation. Chem Soc Rev 2022; 51:9243-9261. [PMID: 36285735 PMCID: PMC9669245 DOI: 10.1039/d2cs00362g] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Proteolysis-targeting chimeras (PROTACs) and targeted covalent inhibitors (TCIs) are currently two exciting strategies in the fields of chemical biology and drug discovery. Extensive research in these two fields has been conducted, and significant progress in these fields has resulted in many clinical candidates, some of which have been approved by FDA. Recently, a novel concept termed covalent PROTACs that combine these two strategies has emerged and gained an increasing interest in the past several years. Herein, we briefly review and highlight the mechanism and advantages of TCIs and PROTACs, respectively, and the recent development of covalent PROTACs using irreversible and reversible covalent chemistry.
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Affiliation(s)
- Dong Lu
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
| | - Xin Yu
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
| | - Hanfeng Lin
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
| | - Ran Cheng
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
| | - Erika Y Monroy
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
| | - Xiaoli Qi
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
| | - Meng C Wang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA
- Huffington Center on Aging, Baylor College of Medicine, Houston TX 77030, USA
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston TX 77030, USA
| | - Jin Wang
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston TX 77030, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston TX 77030, USA
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Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development. Molecules 2022; 27:molecules27227728. [PMID: 36431829 PMCID: PMC9694382 DOI: 10.3390/molecules27227728] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/04/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
Cysteine is one of the least abundant amino acids in proteins of many organisms, which plays a crucial role in catalysis, signal transduction, and redox regulation of gene expression. The thiol group of cysteine possesses the ability to perform nucleophilic and redox-active functions that are not feasible for other natural amino acids. Cysteine is the most common covalent amino acid residue and has been shown to react with a variety of warheads, especially Michael receptors. These unique properties have led to widespread interest in this nucleophile, leading to the development of a variety of cysteine-targeting warheads with different chemical compositions. Herein, we summarized the various covalent warheads targeting cysteine residue and their application in drug development.
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Li T, Zhang G, Zhang X, Lin H, Liu Q. The 8p11 myeloproliferative syndrome: Genotypic and phenotypic classification and targeted therapy. Front Oncol 2022; 12:1015792. [PMID: 36408177 PMCID: PMC9669583 DOI: 10.3389/fonc.2022.1015792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/10/2022] [Indexed: 10/05/2023] Open
Abstract
EMS(8p11 myeloproliferative syndrome, EMS) is an aggressive hematological neoplasm with/without eosinophilia caused by a rearrangement of the FGFR1 gene at 8p11-12. It was found that all cases carry chromosome abnormalities at the molecular level, not only the previously reported chromosome translocation and insertion but also a chromosome inversion. These abnormalities produced 17 FGFR1 fusion genes, of which the most common partner genes are ZNF198 on 13q11-12 and BCR of 22q11.2. The clinical manifestations can develop into AML (acute myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma), CML (chronic myeloid leukemia), CMML (chronic monomyelocytic leukemia), or mixed phenotype acute leukemia (MPAL). Most patients are resistant to traditional chemotherapy, and a minority of patients achieve long-term clinical remission after stem cell transplantation. Recently, the therapeutic effect of targeted tyrosine kinase inhibitors (such as pemigatinib and infigratinib) in 8p11 has been confirmed in vitro and clinical trials. The TKIs may become an 8p11 treatment option as an alternative to hematopoietic stem cell transplantation, which is worthy of further study.
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Affiliation(s)
- Taotao Li
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Gaoling Zhang
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoling Zhang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Disease, First Hospital, Jilin University, Changchun, China
| | - Hai Lin
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Qiuju Liu
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
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Zhang G, Yan B, Guo Y, Yang H, Li X, Li J. Case Report: A patient with the rare third-generation TKI-resistant mutation EGFR L718Q who responded to afatinib plus cetuximab combination therapy. Front Oncol 2022; 12:995624. [PMID: 36387265 PMCID: PMC9659857 DOI: 10.3389/fonc.2022.995624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 10/13/2022] [Indexed: 12/05/2022] Open
Abstract
Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, almonertinib and furmonertinib, overcome the mechanisms of resistance to first-generation inhibitors (such as gefitinib, erlotinib and icotinib) by incorporating an acrylamide group that alkylates the Cys797 of EGFR T790M. However, drug resistance is inevitable, even for third-generation TKIs. Screening for drug-resistant mutations by repeat biopsy and repeat gene sequencing is necessary after TKI treatment. Among various third-generation TKI-resistant mutations, secondary mutation of the L718 residue of EGFR exon 18 was found in approximately 8% of patients and is responsible for drug resistance in vitro and in vivo. Furthermore, there is limited clinical experience of targeted therapy for this mutation. Herein, we report for the first time that afatinib and cetuximab combination therapy can overcome such drug resistance.
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Jia T, Miao R, Lin J, Zhang C, Zeng L, Zhang J, Shao J, Pan Z, Wang H, Zhu H, Cheng W. Design, synthesis and biological evaluation of novel tumor hypoxia-activated EGFR tyrosine kinase inhibitors. Bioorg Chem 2022; 129:106138. [PMID: 36115310 DOI: 10.1016/j.bioorg.2022.106138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/29/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022]
Abstract
Hypoxia is widespread in solid tumors, such as NSCLC, and has become a very attractive target. On the basis of AZD9291 scaffold, novel hypoxia-targeted EGFR inhibitors without the acrylamide warhead but containing hypoxic reductive activation groups were described. Among them, compound JT21 exhibited impressive inhibitory activity (IC50 = 23 nM) against EGFRL858R/T790M and displayed about 21-fold inhibitory activity decrease against EGFRwt. Under hypoxia, JT21 exhibited more significant proliferation inhibitory activities against H1975 cells (IC50 = 7.39 ± 2.20 nM) and HCC827 cells (IC50 = 5.88 ± 0.85 nM) than that of AZD9291, which was about 5 times more effective than normoxia activities. Meanwhile, the weak inhibition effects on A549 and BEAS-2B cells suggested JT21 might be a selective inhibitor for EGFR mutations with low toxicity. Furthermore, JT21 could induce apoptosis of H1975 cells under hypoxia and showed good bio-reductive property.
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Affiliation(s)
- Tingting Jia
- School of Medicine, Zhejiang University City College, Hangzhou 310015, China; Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China
| | - Ruoyang Miao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jiaohua Lin
- Zhejiang Yongtai Technology Co. Ltd, Taizhou 317016, China
| | - Chong Zhang
- School of Medicine, Zhejiang University City College, Hangzhou 310015, China
| | - Linghui Zeng
- School of Medicine, Zhejiang University City College, Hangzhou 310015, China
| | - Jiankang Zhang
- School of Medicine, Zhejiang University City College, Hangzhou 310015, China
| | - Jiaan Shao
- School of Medicine, Zhejiang University City College, Hangzhou 310015, China
| | - Zongfu Pan
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, China
| | - Haiping Wang
- Hangzhou Children's Hospital, Hangzhou, 310014, China.
| | - Huajian Zhu
- School of Medicine, Zhejiang University City College, Hangzhou 310015, China.
| | - Weiyan Cheng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Todsaporn D, Mahalapbutr P, Poo-Arporn RP, Choowongkomon K, Rungrotmongkol T. Structural dynamics and kinase inhibitory activity of three generations of tyrosine kinase inhibitors against wild-type, L858R/T790M, and L858R/T790M/C797S forms of EGFR. Comput Biol Med 2022; 147:105787. [PMID: 35803080 DOI: 10.1016/j.compbiomed.2022.105787] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/25/2022] [Accepted: 06/26/2022] [Indexed: 11/19/2022]
Abstract
Mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), including L858R/T790M double and L858R/T790M/C797S triple mutations, are major causes of acquired resistance towards EGFR targeted drugs. In this work, a combination of comprehensive molecular modeling and in vitro kinase inhibition assay was used to unravel the mutational effects of EGFR on the susceptibility of three generations of EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) in comparison with the wild-type EGFR. The binding affinity of all studied inhibitors towards the double and triple EGFR mutations was in good agreement with the experimental data, ranked in the order of osimertinib > afatinib > dacomitinib > erlotinib > gefitinib. Three hot-spot residues at the hinge region (M790, M793, and C797) were involved in the binding of osimertinib and afatinib, enhancing their inhibitory activity towards mutated EGFRs. Both double and triple EGFR mutations causing erlotinib and gefitinib resistance are mainly caused by the low number of H-bond occupations, the low number of surrounding atoms, and the high number of water molecules accessible to the enzyme active site. According to principal component analysis, the molecular complexation of osimertinib against the two mutated EGFRs was in a closed conformation, whereas that against wild-type EGFR was in an open conformation, resulting in drug resistance. This work paves the way for further design of the novel EGFR inhibitors to overcome drug resistance mechanisms.
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Affiliation(s)
- Duangjai Todsaporn
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Panupong Mahalapbutr
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - Rungtiva P Poo-Arporn
- Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
| | - Thanyada Rungrotmongkol
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand; Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.
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30
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Zhang G, Yan B, Guo Y, Yang H, Li J. "Sandwich" Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients. Front Oncol 2022; 12:952939. [PMID: 35903676 PMCID: PMC9321780 DOI: 10.3389/fonc.2022.952939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/16/2022] [Indexed: 02/03/2023] Open
Abstract
EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.
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Affiliation(s)
- Guoqing Zhang
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Beibei Yan
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Guo
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hang Yang
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jindong Li
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Design, synthesis and mechanistic studies of novel imidazo[1,2-a]pyridines as anticancer agents. Bioorg Chem 2022; 128:106042. [PMID: 35878430 DOI: 10.1016/j.bioorg.2022.106042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/16/2022] [Accepted: 07/17/2022] [Indexed: 11/20/2022]
Abstract
Herein, the design, synthesis and mechanistic study of five series of imidazo[1,2-a]pyridines 8a-d, 9a-f, 11a-c, 12a-d and 14a-d as anticancer agents were discussed. The cytotoxicity of imidazo[1,2-a]pyridine derivatives was screened against NCI 60 cancer cell lines. The cytotoxicity of compounds 8b, 8c, 9e and 9f was then evaluated against leukemia K-562 cancer cell line and normal lung fibroblasts (WI38). The hydrazone derivatives 8b and 8c exhibited significant cytotoxic activities against the leukemia K-562 cancer cell line with good safety margins (IC50 = 2.91 µM, SI = 8.32 and IC50 = 1.09 µM, SI = 10.54, respectively). In addition, compounds 8b, 8c, 9e and 9f were tested for their EGFR and COX-2 inhibitory activities. The hydrazone derivatives 8b and 8c were the most active EGFR inhibitors with IC50 values of 0.123 and 0.072 µM, respectively. Compound 8c selectively inhibited COX-2 (IC50 = 1.09 µM, SI = 13.78). Moreover, the potential of compound 8c to induce apoptosis in leukemia K-562 cell line was determined. Compound 8c showed a pre-G1 apoptosis and a growth arrest of leukemia K-562 cell line at G1 phase of cell cycle. Also, compound 8c was able to induce caspase-3 overexpression (6.98 folds), if compared to control. Finally, molecular docking studies and physicochemical properties calculation of compounds 8b, 8c, 9e and 9f were carried out to explain the biological data and to predict bioavailability of the most active compounds.
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da Silva-Oliveira RJ, Gomes INF, da Silva LS, Lengert AVH, Laus AC, Melendez ME, Munari CC, Cury FDP, Longato GB, Reis RM. Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines. Int J Mol Sci 2022; 23:ijms23147774. [PMID: 35887120 PMCID: PMC9317664 DOI: 10.3390/ijms23147774] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 01/27/2023] Open
Abstract
Background: EGFR mutations are present in approximately 15−50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype. Methods: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors’ activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index. Results: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 < 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored. Conclusions: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines.
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Affiliation(s)
- Renato José da Silva-Oliveira
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
- Correspondence: (R.J.d.S.-O.); (R.M.R.)
| | - Izabela Natalia Faria Gomes
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Luciane Sussuchi da Silva
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - André van Helvoort Lengert
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Ana Carolina Laus
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Matias Eliseo Melendez
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Carla Carolina Munari
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Fernanda de Paula Cury
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Giovanna Barbarini Longato
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
| | - Rui Manuel Reis
- Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; (I.N.F.G.); (L.S.d.S.); (A.v.H.L.); (A.C.L.); (M.E.M.); (C.C.M.); (F.d.P.C.); (G.B.L.)
- Life and Health Sciences Research Institute (ICVS) Medical School, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s-PT Government Associate Laboratory, 4710-057 Braga, Portugal
- Correspondence: (R.J.d.S.-O.); (R.M.R.)
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Bosáková V, De Zuani M, Sládková L, Garlíková Z, Jose SS, Zelante T, Hortová Kohoutková M, Frič J. Lung Organoids—The Ultimate Tool to Dissect Pulmonary Diseases? Front Cell Dev Biol 2022; 10:899368. [PMID: 35912110 PMCID: PMC9326165 DOI: 10.3389/fcell.2022.899368] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/24/2022] [Indexed: 11/15/2022] Open
Abstract
Organoids are complex multicellular three-dimensional (3D) in vitro models that are designed to allow accurate studies of the molecular processes and pathologies of human organs. Organoids can be derived from a variety of cell types, such as human primary progenitor cells, pluripotent stem cells, or tumor-derived cells and can be co-cultured with immune or microbial cells to further mimic the tissue niche. Here, we focus on the development of 3D lung organoids and their use as disease models and drug screening tools. We introduce the various experimental approaches used to model complex human diseases and analyze their advantages and disadvantages. We also discuss validation of the organoids and their physiological relevance to the study of lung diseases. Furthermore, we summarize the current use of lung organoids as models of host-pathogen interactions and human lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or SARS-CoV-2 infection. Moreover, we discuss the use of lung organoids derived from tumor cells as lung cancer models and their application in personalized cancer medicine research. Finally, we outline the future of research in the field of human induced pluripotent stem cell-derived organoids.
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Affiliation(s)
- Veronika Bosáková
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Marco De Zuani
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
| | - Lucie Sládková
- Institute of Hematology and Blood Transfusion, Prague, Czechia
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czechia
| | - Zuzana Garlíková
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
| | - Shyam Sushama Jose
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
| | - Teresa Zelante
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Jan Frič
- International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czechia
- Institute of Hematology and Blood Transfusion, Prague, Czechia
- *Correspondence: Jan Frič,
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Wu X, Wang J, Liang Q, Tong R, Huang J, Yang X, Xu Y, Wang W, Sun M, Shi J. Recent progress on FAK inhibitors with dual targeting capabilities for cancer treatment. Biomed Pharmacother 2022; 151:113116. [PMID: 35598365 DOI: 10.1016/j.biopha.2022.113116] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/30/2022] [Accepted: 05/10/2022] [Indexed: 02/08/2023] Open
Abstract
Focal adhesion kinase (FAK, also known as PTK2) is a tyrosine kinase that regulates integrin and growth factor signaling pathways and is involved in the migration, proliferation and survival of cancer cells. FAK is a promising target for cancer treatment. Many small molecule FAK inhibitors have been identified and proven in both preclinical and clinical studies to be effective inhibitors of tumor growth and metastasis. There are many signaling pathways, such as those involving FAK, Src, AKT, MAPK, PI3K, and EGFR/HER-2, that provide survival signals in cancer cells. Dual inhibitors that simultaneously block FAK and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, the antitumor mechanisms and research status of dual inhibitors of FAK and other targets, such as Pyk2, IGF-IR, ALK, VEGFR-3, JAK2, EGFR, S6K1, and HDAC2, are summarized, providing new ideas for the development of effective FAK dual-target preparations.
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Affiliation(s)
- Xianbo Wu
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, Sichuan 610041, China
| | - Jie Wang
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550002, China
| | - Qi Liang
- College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Rongsheng Tong
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Jianli Huang
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550002, China
| | - Xinwei Yang
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, Sichuan 610041, China
| | - Yihua Xu
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China
| | - Wenjing Wang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
| | - Minghan Sun
- Central of Reproductive Medicine, Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
| | - Jianyou Shi
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
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Zhou H, Fu H, Liu H, Shao X, Cai W. Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations. Front Mol Biosci 2022; 9:922839. [PMID: 35707225 PMCID: PMC9189374 DOI: 10.3389/fmolb.2022.922839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
The emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. However, the mechanism of the enhancement of the binding affinity of ATP to EGFR, which is of paramount importance for the development of new inhibitors, is still unclear. In this work, to explore the detailed mechanism of the drug resistance due to the T790M mutation, molecular dynamics simulations and absolute binding free energy calculations have been performed. The results show that the binding affinity of ATP with respect to the L858R/T790M mutant is higher compared with the L858R mutant, in good agreement with experiments. Further analysis demonstrates that the T790M mutation significantly changes the van der Waals interaction of ATP and the binding site. We also find that the favorable binding of ATP to the L858R/T790M mutant, compared with the L858R mutant, is due to a conformational change of the αC-helix, the A-loop and the P-loop of the latter induced by the T790M mutation. This change makes the interaction of ATP and P-loop, αC-helix in the L858R/T790M mutant higher than that in the L858R mutant, therefore increasing the binding affinity of ATP to EGFR. We believe the drug-resistance mechanism proposed in this study will provide valuable guidance for the design of drugs for NSCLC.
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Affiliation(s)
- Huaxin Zhou
- Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China
| | - Haohao Fu
- Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China
| | - Han Liu
- Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China
| | - Xueguang Shao
- Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China
- *Correspondence: Xueguang Shao, ; Wensheng Cai,
| | - Wensheng Cai
- Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China
- *Correspondence: Xueguang Shao, ; Wensheng Cai,
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Ejigah V, Mandala B, Akala EO. Nanotechnology in the development of small and large molecule tyrosine kinase inhibitors and immunotherapy for the treatment of HER2-positive breast cancer. JOURNAL OF CANCER & METASTASIS RESEARCH 2022; 4:6-22. [PMID: 38966076 PMCID: PMC11223443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
The HER2 receptor tyrosine kinase is a member of the epidermal growth factor receptor family which includes EGFR, HER3 and HER4. They are known to play critical roles in both normal development and cancer. A subset of breast cancers is associated with the HER2 gene, which is amplified and/or overexpressed in 20-25% of invasive breast cancers and is correlated with tumor resistance to chemotherapy, Metastatic Breast Cancer (MBC) and poor patient survival. The advent of receptor tyrosine kinase inhibitors has improved the prognosis of HER2-postive breast cancers; however, HER2+MBC invariably progresses (acquired resistance or de novo resistance). The monoclonal antibody-based drugs (large molecule TKIs) target the extracellular binding domain of HER2; while the small molecule TKIs act intracellularly to inhibit proliferation and survival signals. We reviewed the modes of action of the TKIs with a view to showing which of the TKIs could be combined in nanoparticles to benefit from the power of nanotechnology (reduced toxicity, improved solubility of hydrophobic drugs, long circulation half-lives, circumventing efflux pumps and preventing capture by the reticuloendothelial system (mononuclear phagocyte system). Nanotherapeutics also mediate the synchronization of the pharmacokinetics and biodistribution of multiple drugs incorporated in the nanoparticles. Novel TKIs that are currently under investigation with or without nanoparticle delivery are mentioned, and nano-based strategies to improve their delivery are suggested. Immunotherapies currently in clinical practice, clinical trials or at the preclinical stage are discussed. However, immunotherapy only works well in relatively small subsets of patients. Combining nanomedicine with immunotherapy can boost therapeutic outcomes, by turning "cold" non-immunoresponsive tumors and metastases into "hot" immunoresponsive lesions.
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Affiliation(s)
- Victor Ejigah
- Department of Pharmaceutical Sciences, College of Pharmacy Howard University Washington DC, Center for Drug Research and Development (CDRD), USA
| | - Bharathi Mandala
- Department of Pharmaceutical Sciences, College of Pharmacy Howard University Washington DC, Center for Drug Research and Development (CDRD), USA
| | - Emmanuel O Akala
- Department of Pharmaceutical Sciences, College of Pharmacy Howard University Washington DC, Center for Drug Research and Development (CDRD), USA
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Abstract
Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceutical industry over concerns about the potential for toxicity. A resurgence has occurred driven by the clinical success of targeted covalent inhibitors (TCIs), with eight drugs approved over the past decade. The opportunity to create unique drugs by exploiting the covalent mechanism of action has enabled clinically decisive target product profiles to be achieved. TCIs have revolutionized the treatment paradigm for non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight the clinical and financial success of this class of drugs and provide early insight into toxicity, a key factor that had hindered progress in the field. Further innovation in the TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, and cancer, highlights the broad opportunity to deliver a new generation of breakthrough therapies.
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Affiliation(s)
- Juswinder Singh
- Ankaa Therapeutics, M2D2 Incubator, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, United States
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38
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Joy F, Peter F, Gokul PC, Nizam A, Chinnam S. UV-Promoted Metal- and Photocatalyst-Free Direct Conversion of Aromatic Aldehydes to Nitriles. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1070428022030174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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39
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EGFR signaling pathway as therapeutic target in human cancers. Semin Cancer Biol 2022; 85:253-275. [PMID: 35427766 DOI: 10.1016/j.semcancer.2022.04.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/12/2022] [Accepted: 04/04/2022] [Indexed: 02/08/2023]
Abstract
Epidermal Growth Factor Receptor (EGFR) enacts major roles in the maintenance of epithelial tissues. However, when EGFR signaling is altered, it becomes the grand orchestrator of epithelial transformation, and hence one of the most world-wide studied tyrosine kinase receptors involved in neoplasia, in several tissues. In the last decades, EGFR-targeted therapies shaped the new era of precision-oncology. Despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us. Studies investigating the function of this protein in solid malignancies have revealed numerous ways how tumor cells dysregulate EGFR function. Starting from preclinical models (cell lines, organoids, murine models) and validating in clinical specimens, EGFR-related oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread enriching the therapeutic portfolios, were identified. Focusing on non-small cell lung cancer (NSCLC), where EGFR mutations are major players in the adenocarcinoma subtype, we will go over the most relevant discoveries that led us to understand EGFR and beyond, and highlight how they revolutionized cancer treatment by expanding the therapeutic arsenal at our disposal.
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40
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Lone SN, Nisar S, Masoodi T, Singh M, Rizwan A, Hashem S, El-Rifai W, Bedognetti D, Batra SK, Haris M, Bhat AA, Macha MA. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer 2022; 21:79. [PMID: 35303879 PMCID: PMC8932066 DOI: 10.1186/s12943-022-01543-7] [Citation(s) in RCA: 379] [Impact Index Per Article: 126.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/21/2022] [Indexed: 02/07/2023] Open
Abstract
Over the past decade, invasive techniques for diagnosing and monitoring cancers are slowly being replaced by non-invasive methods such as liquid biopsy. Liquid biopsies have drastically revolutionized the field of clinical oncology, offering ease in tumor sampling, continuous monitoring by repeated sampling, devising personalized therapeutic regimens, and screening for therapeutic resistance. Liquid biopsies consist of isolating tumor-derived entities like circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc., present in the body fluids of patients with cancer, followed by an analysis of genomic and proteomic data contained within them. Methods for isolation and analysis of liquid biopsies have rapidly evolved over the past few years as described in the review, thus providing greater details about tumor characteristics such as tumor progression, tumor staging, heterogeneity, gene mutations, and clonal evolution, etc. Liquid biopsies from cancer patients have opened up newer avenues in detection and continuous monitoring, treatment based on precision medicine, and screening of markers for therapeutic resistance. Though the technology of liquid biopsies is still evolving, its non-invasive nature promises to open new eras in clinical oncology. The purpose of this review is to provide an overview of the current methodologies involved in liquid biopsies and their application in isolating tumor markers for detection, prognosis, and monitoring cancer treatment outcomes.
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Affiliation(s)
- Saife N Lone
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Arshi Rizwan
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Sheema Hashem
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
| | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA
| | - Davide Bedognetti
- Cancer Research Department, Research Branch, Sidra Medicince, Doha, Qatar
- Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE 68198, Omaha, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center , Omaha, NE 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, University of Nebraska Medical Center, NE 68198, Omaha, USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
- Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Ajaz A Bhat
- Laboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, PO BOX 26999, Doha, Qatar.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, (IUST), 192122, Awantipora, Jammu & Kashmir, India.
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41
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Akher FB, Farrokhzadeh A, Ravenscroft N, Kuttel MM. Deciphering the Mechanism of Binding Selectivity of Chlorofluoroacetamide-Based Covalent Inhibitors toward L858R/T790M Resistance Mutation. J Chem Inf Model 2022; 62:997-1013. [PMID: 35119858 DOI: 10.1021/acs.jcim.1c01399] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Covalent modification of the oncogenic mutant epidermal growth factor receptor (EGFR) by small molecules is an efficient strategy for achieving an enhanced and sustained pharmacological effect in the treatment of non-small-cell lung cancer. NSP-037 (18), an irreversible inhibitor of the L858R/T790M double-mutant EGFR (EGFRDM) using α-chlorofluoroacetamide (CFA) as a novel warhead, has seven times the inhibition selectivity for EGFRDM over the wild type (EGFRWT), as compared to clinically approved osimertinib (7). Here, we employ multiple computational approaches to elucidate the mechanism underlining this improved selectivity, as well as the effect of CFA on the selectivity enhancement of inhibitor 18 over 7. We find that EGFRDM undergoes significantly larger conformational changes than EGFRWT upon binding to 18. The conformational stability of the diamine side chain and the CFA motif of 18 in the orthosteric site of EGFRDM is identified as key for the disparate binding mechanism and inhibitory prowess of 18 with respect to EGFRWT and EGFRDM and 18's higher selectivity than 7. The binding free energy of the 18-bound complexes is -6.38 kcal/mol greater than that of the 7-bound complexes, explaining the difference in selectivity of these inhibitors. Further, free energy decomposition analysis indicates that the electrostatic contribution of key residues plays an important role in the 18-bound complexes. QM/MM calculations show that the most favored mechanism for the Cys797 alkylation reaction is the direct displacement mechanism through a CFA-based inhibitor, producing a reaction with the lowest energy barrier and most stable product.
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Affiliation(s)
- Farideh Badichi Akher
- Department of Computer Science, University of Cape Town, Cape Town 7700, South Africa.,Department of Chemistry, University of Cape Town, Cape Town 7700, South Africa.,Department of Biochemistry & Molecular Biology, University of Dalhousie, Halifax, NS B3H 4R2, Canada
| | | | - Neil Ravenscroft
- Department of Chemistry, University of Cape Town, Cape Town 7700, South Africa
| | - Michelle M Kuttel
- Department of Computer Science, University of Cape Town, Cape Town 7700, South Africa
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Wittlinger F, Heppner DE, To C, Günther M, Shin BH, Rana JK, Schmoker AM, Beyett TS, Berger LM, Berger BT, Bauer N, Vasta JD, Corona CR, Robers MB, Knapp S, Jänne PA, Eck MJ, Laufer SA. Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites. J Med Chem 2022; 65:1370-1383. [PMID: 34668706 PMCID: PMC9255384 DOI: 10.1021/acs.jmedchem.1c00848] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.
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Affiliation(s)
- Florian Wittlinger
- Institute for Pharmaceutical Sciences Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen
| | - David E. Heppner
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA),Current Address: Department of Chemistry, University at Buffalo, State University of New York, 515 Natural Science Complex, Buffalo, NY 14260-3000
| | - Ciric To
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Marcel Günther
- Institute for Pharmaceutical Sciences Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen
| | - Bo Hee Shin
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Jaimin K. Rana
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Anna M. Schmoker
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Tyler S. Beyett
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Lena M. Berger
- Structural Genomics Consortium, Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany,Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
| | - Benedict-Tilman Berger
- Structural Genomics Consortium, Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany,Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
| | - Nicolas Bauer
- Structural Genomics Consortium, Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany,Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
| | - James D. Vasta
- Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711, USA
| | - Cesear R. Corona
- Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711, USA
| | - Matthew B. Robers
- Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711, USA
| | - Stefan Knapp
- Structural Genomics Consortium, Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany,Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
| | - Pasi A. Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA),Belfer Center for Applied Cancer Science, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Michael J. Eck
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA 02215 (USA)
| | - Stefan A. Laufer
- Institute for Pharmaceutical Sciences Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen,Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, 72076 Tübingen, Germany,Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany
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43
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Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors. Molecules 2022; 27:molecules27030819. [PMID: 35164092 PMCID: PMC8838133 DOI: 10.3390/molecules27030819] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug’s ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
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44
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Dent P. Cell Signaling and Translational Developmental Therapeutics. COMPREHENSIVE PHARMACOLOGY 2022. [PMCID: PMC7538147 DOI: 10.1016/b978-0-12-820472-6.00002-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The relationships between drug pharmacodynamics and subsequent changes in cellular signaling processes are complex. Many in vitro cell signaling studies often use drug concentrations above physiologically safe drug levels achievable in a patient's plasma. Drug companies develop agents to inhibit or modify the activities of specific target enzymes, often without a full consideration that their compounds have additional unknown targets. These two negative sequelae, when published together, become impediments against successful developmental therapeutics and translation because this data distorts our understanding of signaling mechanisms and reduces the probability of successfully translating drug-based concepts from the bench to the bedside. This article will discuss cellular signaling in isolation and as it relates to extant single and combined therapeutic drug interventions. This will lead to a hypothetical series standardized sequential approaches describing a rigorous concept to drug development and clinical translation.
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Lu X, Smaill JB, Patterson AV, Ding K. Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors. J Med Chem 2021; 65:58-83. [PMID: 34962782 DOI: 10.1021/acs.jmedchem.1c01719] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which have the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics of CKIs and discovery of additional irreversible and reversible-covalent cysteine-targeted warheads has inspired the development of this area. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative CKIs, which are categorized by the location of the target cysteine within seven main regions of the kinase: the front region, the glycine rich loop (P-loop), the hinge region, the DFG region, the activation loop (A-loop), the catalytic loop (C-loop), and the remote loop. The emphasis is placed on the design and optimization strategies of CKIs that are generated by addition of a warhead to a reversible lead/inhibitor scaffold. In addition, we address the challenges facing this area of drug discovery.
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Affiliation(s)
- Xiaoyun Lu
- School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Jeff B Smaill
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Adam V Patterson
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Ke Ding
- School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
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Tang X, Cheng L, Li G, Yan YM, Su F, Huang DL, Zhang S, Liu Z, Qian M, Li J, Cheng YX, Liu B. A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer. Commun Biol 2021; 4:1391. [PMID: 34903832 PMCID: PMC8668973 DOI: 10.1038/s42003-021-02906-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 11/16/2021] [Indexed: 11/10/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a deadly and highly prevalent malignancy. Targeting activated-EGFR mutations in NSCLC via EGFR tyrosine kinase inhibitor (EGFR-TKI) initially achieves a profound therapeutic response, but resistance frequently evolves, reducing treatment options. Here, we present a small-molecule compound D6 which selectively inhibits tumor cell growth and migration in NSCLC cells with EGFR-TKI-resistant T790M-EGFR-activated mutations (T790M-EGFR-AM), e.g., L858R/T790M, 19Del/T790M and L858R/T790M/C797S. D6 mimics a natural product isolated from the roots of Codonopsis pilosula and selectively competes with T790M-EGFR-AM to bind to HSP90, thus facilitating the ubiquitination dependent proteasomal degradation of T790M-EGFR-AM. By contrast, D6 has little impact on typical HSP90 chaperone activity, suggesting low systemic toxicity. Promisingly, D6 combined with erlotinib or osimertinib shows efficacy in overcoming the EGFR-TKIs-resistance in NSCLCs. Our study raises an alternative strategy to overcome T790M-mediated EGFR-TKI resistance in NSCLC via targeting the protein-protein interaction of HSP90 and T790M-EGFR by intervention with D6.
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Affiliation(s)
- Xiaolong Tang
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China.
| | - Lizhi Cheng
- grid.263488.30000 0001 0472 9649Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China
| | - Guo Li
- grid.452223.00000 0004 1757 7615Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Yong-Ming Yan
- grid.263488.30000 0001 0472 9649Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China
| | - Fengting Su
- grid.263488.30000 0001 0472 9649Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China
| | - Dan-Ling Huang
- grid.263488.30000 0001 0472 9649Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China
| | - Shuping Zhang
- grid.452223.00000 0004 1757 7615Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Zuojun Liu
- grid.263488.30000 0001 0472 9649Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China
| | - Minxian Qian
- grid.263488.30000 0001 0472 9649Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China
| | - Ji Li
- grid.452223.00000 0004 1757 7615Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Yong-Xian Cheng
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China.
| | - Baohua Liu
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences; Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China. .,Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University, Shenzhen, China. .,National Engineering Research Center for Biotechnology (Shenzhen); Marshall Laboratory of Biomedical Engineering; International Cancer Center, Shenzhen University, Shenzhen, China. .,Shenzhen Bay Laboratory, Shenzhen, China.
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Alanazi MM, Eissa IH, Alsaif NA, Obaidullah AJ, Alanazi WA, Alasmari AF, Albassam H, Elkady H, Elwan A. Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers. J Enzyme Inhib Med Chem 2021; 36:1760-1782. [PMID: 34340610 PMCID: PMC8344243 DOI: 10.1080/14756366.2021.1956488] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC50 of 3.2 nM very close to positive control sorafenib (IC50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC50 of 7.7 and 4.5 µM in comparison to sorafenib (IC50 = 3.51 and 2.17 µM). In addition, compounds 28, 30f, 30i, and 31b exhibited excellent VEGFR-2 inhibition activities (IC50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a. Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles.
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Affiliation(s)
- Mohammed M. Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ibrahim H. Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Nawaf A. Alsaif
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad J. Obaidullah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Wael A. Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah F. Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hussam Albassam
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hazem Elkady
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Alaa Elwan
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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Abourehab MAS, Alqahtani AM, Youssif BGM, Gouda AM. Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism. Molecules 2021; 26:6677. [PMID: 34771085 PMCID: PMC8587155 DOI: 10.3390/molecules26216677] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/28/2021] [Accepted: 11/02/2021] [Indexed: 02/06/2023] Open
Abstract
Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.
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Affiliation(s)
- Mohammed A. S. Abourehab
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Alaa M. Alqahtani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Bahaa G. M. Youssif
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;
| | - Ahmed M. Gouda
- Department of Medicinal Chemistry, Faculty of pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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Wang P, Li Y, Lv D, Yang L, Ding L, Zhou J, Hong W, Chen Y, Zhang D, He S, Zhou J, Wang K. Mefatinib as first-line treatment of patients with advanced EGFR-mutant non-small-cell lung cancer: a phase Ib/II efficacy and biomarker study. Signal Transduct Target Ther 2021; 6:374. [PMID: 34719670 PMCID: PMC8558340 DOI: 10.1038/s41392-021-00773-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 12/16/2022] Open
Abstract
EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.
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Affiliation(s)
- Pingli Wang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yuping Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dongqing Lv
- Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Lingge Yang
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
| | - Liren Ding
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jianya Zhou
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Hong
- Department of Oncology and Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China
| | - Youfei Chen
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Dongqing Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Susu He
- Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jianying Zhou
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
| | - Kai Wang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China.
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50
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Pang XJ, Liu XJ, Liu Y, Liu WB, Li YR, Yu GX, Tian XY, Zhang YB, Song J, Jin CY, Zhang SY. Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy. Molecules 2021; 26:molecules26144250. [PMID: 34299525 PMCID: PMC8308130 DOI: 10.3390/molecules26144250] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/30/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through “proteolysis targeting chimera” (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.
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Affiliation(s)
- Xiao-Jing Pang
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
| | - Xiu-Juan Liu
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
| | - Yuan Liu
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
| | - Wen-Bo Liu
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
| | - Yin-Ru Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Y.-R.L.); (G.-X.Y.); (X.-Y.T.)
| | - Guang-Xi Yu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Y.-R.L.); (G.-X.Y.); (X.-Y.T.)
| | - Xin-Yi Tian
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Y.-R.L.); (G.-X.Y.); (X.-Y.T.)
| | - Yan-Bing Zhang
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
| | - Jian Song
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Y.-R.L.); (G.-X.Y.); (X.-Y.T.)
- Correspondence: (J.S.); (C.-Y.J.); (S.-Y.Z.)
| | - Cheng-Yun Jin
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Y.-R.L.); (G.-X.Y.); (X.-Y.T.)
- Correspondence: (J.S.); (C.-Y.J.); (S.-Y.Z.)
| | - Sai-Yang Zhang
- Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; (X.-J.P.); (X.-J.L.); (Y.L.); (W.-B.L.); (Y.-B.Z.)
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Y.-R.L.); (G.-X.Y.); (X.-Y.T.)
- Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China
- Correspondence: (J.S.); (C.-Y.J.); (S.-Y.Z.)
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