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Chaudhary B, Arya P, Sharma V, Kumar P, Singla D, Grewal AS. Targeting anti-apoptotic mechanisms in tumour cells: Strategies for enhancing Cancer therapy. Bioorg Chem 2025; 159:108388. [PMID: 40107036 DOI: 10.1016/j.bioorg.2025.108388] [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: 01/23/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming "dependent" on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.
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Affiliation(s)
- Benu Chaudhary
- Shri Ram College of Pharmacy, Ramba, Karnal, Haryana, India
| | - Preeti Arya
- Shri Ram College of Pharmacy, Ramba, Karnal, Haryana, India
| | - Vikas Sharma
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India
| | - Parveen Kumar
- NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan, India
| | - Deepak Singla
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India
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Madhukar G, Haque MA, Khan S, Kim JJ, Danishuddin. E3 ubiquitin ligases and their therapeutic potential in disease Management. Biochem Pharmacol 2025; 236:116875. [PMID: 40120724 DOI: 10.1016/j.bcp.2025.116875] [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: 11/27/2024] [Revised: 02/05/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribution to targeted degradation strategies while highlighting the need for further research to overcome current limitations and enhance therapeutic efficacy.
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Affiliation(s)
- Geet Madhukar
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Md Azizul Haque
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
| | - Shawez Khan
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark
| | - Jong-Joo Kim
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
| | - Danishuddin
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
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3
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Twarda-Clapa A. An update patent review of MDM2-p53 interaction inhibitors (2019-2023). Expert Opin Ther Pat 2024; 34:1177-1198. [PMID: 39435470 DOI: 10.1080/13543776.2024.2419836] [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: 08/13/2024] [Revised: 09/19/2024] [Accepted: 10/16/2024] [Indexed: 10/23/2024]
Abstract
INTRODUCTION The activity of the major tumor suppressor protein p53 is disrupted in nearly all human cancer types, either by mutations in TP53 gene or by overexpression of its negative regulator, Mouse Double Minute 2 (MDM2). The release of p53 from MDM2 and its homolog MDM4 with inhibitors based on different chemistries opened up a prospect for a broad, non-genotoxic anticancer therapy. AREAS COVERED This article reviews the patents and patent applications between years 2019 and 2023 in the field of MDM2-p53 interaction inhibitors. The newly reported molecules searched in Espacenet, Google Patents, and PubMed were grouped into five general categories: compounds having single-ring, multi-ring, or spiro-oxindole scaffolds, peptide derivatives, and proteolysis-targeting chimeras (PROTACs). The article also presents the progress of MDM2 antagonists of various structures in recruiting or completed cancer clinical trials. EXPERT OPINION Despite 20 years of intensive studies after the discovery of the first-in-class small-molecule inhibitor, Nutlin-3, no drugs targeting MDM2-p53 interaction have reached the market. Nevertheless, more than 10 compounds are still being evaluated in clinics, both as standalone drugs and in combinations with other targeted therapies or standard chemotherapy agents, including two inhibitors in phase 3 studies and two compounds granted orphan-drug/fast-track designation by the FDA.
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Affiliation(s)
- Aleksandra Twarda-Clapa
- Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Lodz, Poland
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DiNardo CD, Olin R, Wang ES, Skikne B, Rosenthal J, Kumar P, Sumi H, Hizukuri Y, Hong Y, Patel P, Seki T, Duan T, Lesegretain A, Andreeff M. Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies. Cancer Med 2024; 13:e70028. [PMID: 39030997 PMCID: PMC11258486 DOI: 10.1002/cam4.70028] [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: 02/29/2024] [Revised: 05/29/2024] [Accepted: 07/07/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. METHODS This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. RESULTS Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. INTERPRETATION Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.
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Affiliation(s)
- Courtney D. DiNardo
- Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Rebecca Olin
- University of CaliforniaSan FranciscoCaliforniaUSA
| | - Eunice S. Wang
- Roswell Park Comprehensive Care CenterBuffaloNew YorkUSA
| | - Barry Skikne
- University of Kansas Medical CenterKansas CityKansasUSA
| | | | | | | | | | - Ying Hong
- Daiichi Sankyo Inc.Basking RidgeNew JerseyUSA
| | - Parul Patel
- Daiichi Sankyo Inc.Basking RidgeNew JerseyUSA
| | | | - Tao Duan
- Daiichi Sankyo Inc.Basking RidgeNew JerseyUSA
| | | | - Michael Andreeff
- Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
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Lu L, Jifu C, Xia J, Wang J. E3 ligases and DUBs target ferroptosis: A potential therapeutic strategy for neurodegenerative diseases. Biomed Pharmacother 2024; 175:116753. [PMID: 38761423 DOI: 10.1016/j.biopha.2024.116753] [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: 03/14/2024] [Revised: 04/30/2024] [Accepted: 05/10/2024] [Indexed: 05/20/2024] Open
Abstract
Ferroptosis is a form of cell death mediated by iron and lipid peroxidation (LPO). Recent studies have provided compelling evidence to support the involvement of ferroptosis in the pathogenesis of various neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD). Therefore, understanding the mechanisms that regulate ferroptosis in NDDs may improve disease management. Ferroptosis is regulated by multiple mechanisms, and different degradation pathways, including autophagy and the ubiquitinproteasome system (UPS), orchestrate the complex ferroptosis response by directly or indirectly regulating iron accumulation or lipid peroxidation. Ubiquitination plays a crucial role as a protein posttranslational modification in driving ferroptosis. Notably, E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are key enzymes in the ubiquitin system, and their dysregulation is closely linked to the progression of NDDs. A growing body of evidence highlights the role of ubiquitin system enzymes in regulating ferroptosis sensitivity. However, reports on the interaction between ferroptosis and ubiquitin signaling in NDDs are scarce. In this review, we first provide a brief overview of the biological processes and roles of the UPS, summarize the core molecular mechanisms and potential biological functions of ferroptosis, and explore the pathophysiological relevance and therapeutic implications of ferroptosis in NDDs. In addition, reviewing the roles of E3s and DUBs in regulating ferroptosis in NDDs aims to provide new insights and strategies for the treatment of NDDs. These include E3- and DUB-targeted drugs and ferroptosis inhibitors, which can be used to prevent and ameliorate the progression of NDDs.
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Affiliation(s)
- Linxia Lu
- College of Basic Medicine, Jiamusi University, Jiamusi 154007, People's Republic of China
| | - Cili Jifu
- College of Basic Medicine, Jiamusi University, Jiamusi 154007, People's Republic of China
| | - Jun Xia
- College of Basic Medicine, Jiamusi University, Jiamusi 154007, People's Republic of China
| | - Jingtao Wang
- College of Basic Medicine, Jiamusi University, Jiamusi 154007, People's Republic of China.
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Sharma AE, Dickson M, Singer S, Hameed MR, Agaram NP. GLI1 Coamplification in Well-Differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases. Mod Pathol 2024; 37:100494. [PMID: 38621503 PMCID: PMC11193651 DOI: 10.1016/j.modpat.2024.100494] [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: 01/25/2024] [Revised: 03/22/2024] [Accepted: 04/08/2024] [Indexed: 04/17/2024]
Abstract
GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.
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Affiliation(s)
- Aarti E Sharma
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pathology, Hospital for Special Surgery, New York, New York
| | - Mark Dickson
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Samuel Singer
- Department of Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Meera R Hameed
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Narasimhan P Agaram
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Shroff RT, Bachini M. Treatment options for biliary tract cancer: unmet needs, new targets and opportunities from both physicians' and patients' perspectives. Future Oncol 2024; 20:1435-1450. [PMID: 38861288 PMCID: PMC11376410 DOI: 10.1080/14796694.2024.2340959] [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: 12/06/2023] [Accepted: 04/05/2024] [Indexed: 06/12/2024] Open
Abstract
Biliary tract cancer (BTC) is a rare cancer with poor prognosis, characterized by considerable pathophysiological and molecular heterogeneity. While this makes it difficult to treat, it also provides targeted therapy opportunities. Current standard-of-care is chemotherapy ± immunotherapy, but several targeted agents have recently been approved. The current investigational landscape in BTC emphasizes the importance of biomarker testing at diagnosis. MDM2/MDMX are important negative regulators of the tumor suppressor p53 and provide an additional target in BTC (∼5-8% of tumors are MDM2-amplified). Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown antitumor activity in preclinical studies and promising results in early clinical trials; enrollment is ongoing in a potential registrational trial for patients with BTC.
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Affiliation(s)
- Rachna T Shroff
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA
| | - Melinda Bachini
- Cholangiocarcinoma Foundation, 5526 West 13400 South, #510, Herriman, UT USA
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Olaoba OT, Adelusi TI, Yang M, Maidens T, Kimchi ET, Staveley-O’Carroll KF, Li G. Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy. Cancers (Basel) 2024; 16:1808. [PMID: 38791887 PMCID: PMC11119842 DOI: 10.3390/cancers16101808] [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: 04/12/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.
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Affiliation(s)
- Olamide T. Olaoba
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Temitope I. Adelusi
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Ming Yang
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Tessa Maidens
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA;
| | - Eric T. Kimchi
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Guangfu Li
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
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Wang W, Albadari N, Du Y, Fowler JF, Sang HT, Xian W, McKeon F, Li W, Zhou J, Zhang R. MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future. Pharmacol Rev 2024; 76:414-453. [PMID: 38697854 PMCID: PMC11068841 DOI: 10.1124/pharmrev.123.001026] [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: 08/22/2023] [Revised: 11/28/2023] [Accepted: 01/16/2024] [Indexed: 05/05/2024] Open
Abstract
Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Najah Albadari
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Yi Du
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Josef F Fowler
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Hannah T Sang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wa Xian
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Frank McKeon
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wei Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Jia Zhou
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
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Rong Z, Zheng K, Chen J, Jin X. The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer. J Cancer Res Clin Oncol 2024; 150:154. [PMID: 38521878 PMCID: PMC10960765 DOI: 10.1007/s00432-024-05659-9] [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: 09/21/2023] [Accepted: 02/20/2024] [Indexed: 03/25/2024]
Abstract
Ubiquitination, a highly adaptable post-translational modification, plays a pivotal role in maintaining cellular protein homeostasis, encompassing cancer chemoresistance-associated proteins. Recent findings have indicated a potential correlation between perturbations in the ubiquitination process and the emergence of drug resistance in CRC cancer. Consequently, numerous studies have spurred the advancement of compounds specifically designed to target ubiquitinates, offering promising prospects for cancer therapy. In this review, we highlight the role of ubiquitination enzymes associated with chemoresistance to chemotherapy via the Wnt/β-catenin signaling pathway, epithelial-mesenchymal transition (EMT), and cell cycle perturbation. In addition, we summarize the application and role of small compounds that target ubiquitination enzymes for CRC treatment, along with the significance of targeting ubiquitination enzymes as potential cancer therapies.
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Affiliation(s)
- Ze Rong
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
| | - Kaifeng Zheng
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China
| | - Jun Chen
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
| | - Xiaofeng Jin
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo, 315211, China.
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11
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Kim D, Min D, Kim J, Kim MJ, Seo Y, Jung BH, Kwon SH, Ro H, Lee S, Sa JK, Lee JY. Nutlin-3a induces KRAS mutant/p53 wild type lung cancer specific methuosis-like cell death that is dependent on GFPT2. J Exp Clin Cancer Res 2023; 42:338. [PMID: 38093368 PMCID: PMC10720203 DOI: 10.1186/s13046-023-02922-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 12/01/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Oncogenic KRAS mutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-class KRAS-G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for other KRAS mutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies. METHODS KRAS mutant, and wildtype NSCLC cells were used in vitro cell analyses. Cell viability, proliferation, and death were measured by MTT, cell counting, colony analyses, and annexin V staining for FACS. Cell tracker dyes were used to investigate cell morphology, which was examined by holotomograpy, and confocal microscopes. RNA sequencing was performed to identify key target molecule or pathway, which was confirmed by qRT-PCR, western blotting, and metabolite analyses by UHPLC-MS/MS. Zebrafish and mouse xenograft model were used for in vivo analysis. RESULTS In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically in KRAS mutant /p53 wild type NSCLC cells. CONCLUSION These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/p53 wild type NSCLC cells.
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Affiliation(s)
- Dasom Kim
- Department of Pathology, Korea University College of Medicine, 73, Goryeodae-Ro, Seongbuk-Gu, Seoul, 02841, South Korea
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea
| | - Dongwha Min
- Department of Pathology, Korea University College of Medicine, 73, Goryeodae-Ro, Seongbuk-Gu, Seoul, 02841, South Korea
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea
| | - Joohee Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea
| | - Min Jung Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea
| | - Yerim Seo
- Center for Advanced Biomolecular Recognition, Korea Instiute of Science and Technology (KIST), Seoul, 02792, Korea
| | - Byung Hwa Jung
- Center for Advanced Biomolecular Recognition, Korea Instiute of Science and Technology (KIST), Seoul, 02792, Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, South Korea
| | - Seung-Hae Kwon
- Korea Basic Science Institute, Seoul Center, Seoul, South Korea
| | - Hyunju Ro
- Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University, Daejeon, 34134, Korea
| | - Seoee Lee
- Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University, Daejeon, 34134, Korea
| | - Jason K Sa
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, South Korea
| | - Ji-Yun Lee
- Department of Pathology, Korea University College of Medicine, 73, Goryeodae-Ro, Seongbuk-Gu, Seoul, 02841, South Korea.
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12
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Zhou Q, Cui X, Zhou H, Guo S, Wu Z, Li L, Zhang J, Feng W, Guo Y, Ma X, Chen Y, Qiu C, Xu M, Deng G. Differentially expressed platelet activation-related genes in dogs with stage B2 myxomatous mitral valve disease. BMC Vet Res 2023; 19:271. [PMID: 38087280 PMCID: PMC10717932 DOI: 10.1186/s12917-023-03789-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/21/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Peripheral blood carries a reservoir of mRNAs that regulate cardiac structure and function potential. Although it is well recognized that the typical symptoms of Myxomatous Mitral Valve Disease (MMVD) stage B2 are long-standing hemodynamic disorder and cardiac structure remodeling caused by mitral regurgitation, the transcriptomic alterations in blood from such dogs are not understood. RESULTS In the present study, comparative high-throughput transcriptomic profiling of blood was performed from normal control (NC) and naturally-occurring MMVD stage B2 (MMVD) dogs. Using Weighted Gene Co-expression Network Analyses (WGCNA), Gene Ontology (GO), and Kyoto Encyclopedia of Gene and Genomes (KEGG), we identified that the turquoise module was the most highly correlated with echocardiographic features and found 64 differentially expressed genes (DEGs) that were significantly enriched in platelet activation related pathways. Therefore, from the turquoise module, we selected five DEGs (MDM2, ROCK1, RIPK1, SNAP23, and ARHGAP35) that, according to real-time qPCR, exhibited significant enrichment in platelet activation related pathways for validation. The results showed that the blood transcriptional abundance of MDM2, ROCK1, RIPK1, and SNAP23 differed significantly (P < 0.01) between NC and MMVD dogs. On the other hand, Correlation Analysis revealed that MDM2, ROCK1, RIPK1, and SNAP23 genes negatively regulated the heart structure parameters, and followed the same trend as observed in WGCNA. CONCLUSION We screened four platelet activation related genes, MDM2, ROCK1, RIPK1, and SNAP23, which may be considered as the candidate biomarkers for the diagnosis of MMVD stage B2. These findings provided new insights into MMVD pathogenesis.
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Affiliation(s)
- Qingqing Zhou
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiang Cui
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Han Zhou
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Shuai Guo
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Zhimin Wu
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Liyang Li
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jinxin Zhang
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Wen Feng
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Yingfang Guo
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiaofei Ma
- Department of Clinical Animal Medicine, College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Yu Chen
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Changwei Qiu
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Ming Xu
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
| | - Ganzhen Deng
- Department of Clinical Animal Medicine, College of Animal Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
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13
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Zhou Z, Zheng K, Zhou S, Yang Y, Chen J, Jin X. E3 ubiquitin ligases in nasopharyngeal carcinoma and implications for therapies. J Mol Med (Berl) 2023; 101:1543-1565. [PMID: 37796337 DOI: 10.1007/s00109-023-02376-7] [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: 11/08/2022] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most common squamous cell carcinomas of the head and neck, and Epstein-Barr virus (EBV) infection is one of the pathogenic factors involved in the oncogenetic development and progression of NPC. E3 ligases, which are key members of the ubiquitin proteasome system (UPS), specifically recognize various oncogenic factors and tumor suppressors and contribute to determining their fate through ubiquitination. Several studies have demonstrated that E3 ligases are aberrantly expressed and mutated in NPC and that these changes are closely associated with the occurrence and progression of NPC. Herein, we aim to thoroughly review the specific action mechanisms by which E3 ligases participate in NPC signaling pathways and discuss their functional relationship with EBV. Moreover, we describe the current progress in and limitations for targeted therapies against E3 ligases in NPC. KEY MESSAGES: • E3 ubiquitin ligases, as members of the UPS system, determine the fate of their substrates and may act either as oncogenic or anti-tumorigenic factors in NPC. • Mutations or dysregulated expression of E3 ubiquitin ligases is closely related to the occurrence, development, and therapeutic sensitivity of NPC, as they play important roles in several signaling pathways affected by EBV infection. • As promising therapeutic targets, E3 ligases may open new avenues for treatment and for improving the prognosis of NPC patients.
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Affiliation(s)
- Zijian Zhou
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China
| | - Kaifeng Zheng
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China
| | - Shao Zhou
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China
| | - Youxiong Yang
- Department of Otolaryngology-Head and Neck Surgery, Ningbo Yinzhou Second Hospital, Ningbo, 315199, China.
| | - Jun Chen
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
| | - Xiaofeng Jin
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center of Ningbo University, Ningbo, 315211, China.
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14
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Singh N, Khan FM, Bala L, Vera J, Wolkenhauer O, Pützer B, Logotheti S, Gupta SK. Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression. BMC Chem 2023; 17:161. [PMID: 37993971 PMCID: PMC10666365 DOI: 10.1186/s13065-023-01082-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 11/08/2023] [Indexed: 11/24/2023] Open
Abstract
Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.
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Affiliation(s)
- Nivedita Singh
- Department of Biochemistry, BBDCODS, BBD University, Lucknow, Uttar Pradesh, India
- MRC Laboratory for Molecular Cell Biology, University College London, London, UK
| | - Faiz M Khan
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
| | - Lakshmi Bala
- Department of Biochemistry, BBDCODS, BBD University, Lucknow, Uttar Pradesh, India
| | - Julio Vera
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Olaf Wolkenhauer
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
- Leibniz Institute for Food Systems Biology, Technical University of Munich, Munich, Germany
- Chhattisgarh Swami Vivekanand Technical University, Bhilai, Chhattisgarh, India
- Stellenbosch Institute of Advanced Study, Wallenberg Research Centre, Stellenbosch University, Stellenbosch, South Africa
| | - Brigitte Pützer
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
| | - Stella Logotheti
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, Athens, Greece
| | - Shailendra K Gupta
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
- Chhattisgarh Swami Vivekanand Technical University, Bhilai, Chhattisgarh, India.
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15
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Alaseem AM. Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens. Saudi Pharm J 2023; 31:101790. [PMID: 37818252 PMCID: PMC10561124 DOI: 10.1016/j.jsps.2023.101790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/12/2023] [Indexed: 10/12/2023] Open
Abstract
Cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments. Combination therapy has emerged as a favorable approach to enhance treatment efficacy and minimize acquired resistance and harmful side effects. The murine double minute 2 (MDM2) protein regulates cellular proliferation and promotes cancer-related activities by negatively regulating the tumor suppressor protein p53. MDM2 aberrations have been reported in a variety of human cancers, making it an appealing target for cancer therapy. As a result, several small-molecule MDM2 inhibitors have been developed and are currently being investigated in clinical studies. Nevertheless, it has been shown that the inhibition of MDM2 alone is inadequate to achieve long-term suppression of tumor growth, thus prompting the need for further investigation into combination therapeutic strategies. In this review, possible clinical and preclinical MDM2 combination inhibitor regimens are thoroughly analyzed and discussed. It provides a rationale for combining MDM2 inhibitors with other therapeutic approaches in the management of cancer, taking into consideration ongoing clinical trials that evaluate the combination of MDM2 inhibitors. The review explores the current status of MDM2 inhibitors in combination with chemotherapy or targeted therapy, as well as promising approach of combining MDM2 inhibitors with immunotherapy. In addition, it investigates the function of PROTACs as MDM2 degraders in cancer treatment. A comprehensive examination of these combination regimens highlights the potential for advancing MDM2-inhibitor therapy and improving clinical outcomes for cancer patients and establishes the foundation for future research and development in this promising area of study.
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Affiliation(s)
- Ali M. Alaseem
- Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
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16
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Scholl S, Roufai DB, Chérif LL, Kamal M. RAIDS atlas of significant genetic and protein biomarkers in cervical cancer. J Gynecol Oncol 2023; 34:e74. [PMID: 37668079 PMCID: PMC10482580 DOI: 10.3802/jgo.2023.34.e74] [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: 12/14/2022] [Revised: 04/07/2023] [Accepted: 06/20/2023] [Indexed: 09/06/2023] Open
Abstract
Loss of function in epigenetic acting genes together with driver alterations in the PIK3CA pathway have been shown significantly associated with poor outcome in cervical squamous cell cancer. More recently, a CoxBoost analysis identified 16 gene alterations and 30 high level activated proteins to be of high interest, due to their association with either good or bad outcome, in the context of treatment received by chemoradiation. The objectives here were to review and confirm the significance of these molecular alterations as suggested by literature reports and to pinpoint alternate treatments options for poor-responders to chemoradiation.
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Affiliation(s)
- Suzy Scholl
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France
- Department of Drug Development and Innovation (D3i), Institut Curie, Saint-Cloud, France.
| | | | - Linda Larbi Chérif
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France
- Department of Drug Development and Innovation (D3i), Institut Curie, Saint-Cloud, France
| | - Maud Kamal
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France
- Department of Drug Development and Innovation (D3i), Institut Curie, Saint-Cloud, France
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17
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LoRusso P, Yamamoto N, Patel MR, Laurie SA, Bauer TM, Geng J, Davenport T, Teufel M, Li J, Lahmar M, Gounder MM. The MDM2-p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study. Cancer Discov 2023; 13:1802-1813. [PMID: 37269344 PMCID: PMC10401071 DOI: 10.1158/2159-8290.cd-23-0153] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/04/2023] [Accepted: 05/23/2023] [Indexed: 06/05/2023]
Abstract
Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). SIGNIFICANCE We report phase Ia data indicating that the oral MDM2-p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.
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Affiliation(s)
- Patricia LoRusso
- Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut
| | - Noboru Yamamoto
- National Cancer Center Hospital, Department of Experimental Therapeutics, Tokyo, Japan
| | - Manish R. Patel
- Sarah Cannon Research Institute, Florida Cancer Specialists and Research Institute, Sarasota, Florida
| | | | - Todd M. Bauer
- Sarah Cannon Research Institute Tennessee Oncology, Nashville, Tennessee
| | - Junxian Geng
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut
| | | | - Michael Teufel
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut
| | - Jian Li
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut
| | - Mehdi Lahmar
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Mrinal M. Gounder
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical School, New York, New York
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18
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Casciano F, Zauli E, Busin M, Caruso L, AlMesfer S, Al-Swailem S, Zauli G, Yu AC. State of the Art of Pharmacological Activators of p53 in Ocular Malignancies. Cancers (Basel) 2023; 15:3593. [PMID: 37509256 PMCID: PMC10377487 DOI: 10.3390/cancers15143593] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/29/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival and corneal tumors, retinoblastoma, uveal melanoma, and intraocular melanoma. As non-selective cancer chemotherapies as well as ionizing radiation can be associated with either poor efficacy or dose-limiting toxicities in the eye, reconstitution of the p53 signaling pathway currently represents an attractive target for cancer therapy. The present review discusses the role of p53 in the pathogenesis of these ocular tumors and outlines the various pharmacological activators of p53 that are currently under investigation for the treatment of ocular malignancies.
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Affiliation(s)
- Fabio Casciano
- Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
| | - Enrico Zauli
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Massimo Busin
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
- Department of Ophthalmology, Ospedali Privati Forlì "Villa Igea", 47122 Forlì, Italy
- Istituto Internazionale per la Ricerca e Formazione in Oftalmologia (IRFO), 47122 Forlì, Italy
| | - Lorenzo Caruso
- Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Saleh AlMesfer
- Research Department, King Khaled Eye Specialistic Hospital, Riyadh 12329, Saudi Arabia
| | - Samar Al-Swailem
- Research Department, King Khaled Eye Specialistic Hospital, Riyadh 12329, Saudi Arabia
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialistic Hospital, Riyadh 12329, Saudi Arabia
| | - Angeli Christy Yu
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
- Department of Ophthalmology, Ospedali Privati Forlì "Villa Igea", 47122 Forlì, Italy
- Istituto Internazionale per la Ricerca e Formazione in Oftalmologia (IRFO), 47122 Forlì, Italy
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19
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Pellot Ortiz KI, Rechberger JS, Nonnenbroich LF, Daniels DJ, Sarkaria JN. MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation. Biomedicines 2023; 11:1879. [PMID: 37509518 PMCID: PMC10377337 DOI: 10.3390/biomedicines11071879] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/28/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.
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Affiliation(s)
| | - Julian S Rechberger
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA
| | - Leo F Nonnenbroich
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), 69120 Heidelberg, Germany
| | - David J Daniels
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
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Gounder MM, Bauer TM, Schwartz GK, Weise AM, LoRusso P, Kumar P, Tao B, Hong Y, Patel P, Lu Y, Lesegretain A, Tirunagaru VG, Xu F, Doebele RC, Hong DS. A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients With Advanced Liposarcoma, Solid Tumors, or Lymphomas. J Clin Oncol 2023; 41:1714-1724. [PMID: 36669146 PMCID: PMC10022862 DOI: 10.1200/jco.22.01285] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/10/2022] [Accepted: 11/29/2022] [Indexed: 01/21/2023] Open
Abstract
PURPOSE This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers. PATIENTS AND METHODS In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and efficacy analyses included all patients who received milademetan. RESULTS Between July 2013 and August 2018, 107 patients were enrolled and received milademetan. The most common grade 3/4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Respective rates at the recommended dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, ie, 3/14 days) were 15.0%, 5.0%, and 0%. Across all cohorts (N = 107), the disease control rate was 45.8% (95% CI, 36.1 to 55.7) and median progression-free survival was 4.0 months (95% CI, 3.4 to 5.7). In the subgroup with dedifferentiated liposarcomas, the disease control rate and median progression-free survival were 58.5% (95% CI, 44.1 to 71.9) and 7.2 months overall (n = 53), and 62.0% (95% CI, 35.4 to 84.8) and 7.4 months with the recommended intermittent schedule (n = 16), respectively. CONCLUSION An intermittent dosing schedule of 3/14 days of milademetan mitigates dose-limiting hematologic abnormalities while maintaining efficacy. Notable single-agent activity with milademetan in dedifferentiated liposarcomas has prompted a randomized phase III trial (MANTRA).
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Affiliation(s)
- Mrinal M. Gounder
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY
| | - Todd M. Bauer
- Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN
| | | | - Amy M. Weise
- Barbara Ann Karmanos Cancer Institute, Karmanos Cancer Institute, Detroit, MI
| | | | | | - Ben Tao
- Daiichi Sankyo Inc, Basking Ridge, NJ
| | - Ying Hong
- Daiichi Sankyo Inc, Basking Ridge, NJ
| | | | - Yasong Lu
- Daiichi Sankyo Inc, Basking Ridge, NJ
| | | | | | - Feng Xu
- Rain Oncology Inc, Newark, CA
| | | | - David S. Hong
- University of Texas M.D. Anderson Cancer Center, Houston, TX
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21
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Wang H, Guo M, Wei H, Chen Y. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct Target Ther 2023; 8:92. [PMID: 36859359 PMCID: PMC9977964 DOI: 10.1038/s41392-023-01347-1] [Citation(s) in RCA: 323] [Impact Index Per Article: 161.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/19/2022] [Accepted: 02/07/2023] [Indexed: 03/03/2023] Open
Abstract
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
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Affiliation(s)
- Haolan Wang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hudie Wei
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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22
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Sampson C, Wang Q, Otkur W, Zhao H, Lu Y, Liu X, Piao H. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy. Clin Transl Med 2023; 13:e1204. [PMID: 36881608 PMCID: PMC9991012 DOI: 10.1002/ctm2.1204] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Ubiquitination is one of the most important post-translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy.
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Affiliation(s)
- Chibuzo Sampson
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina
- University of Chinese Academy of SciencesBeijingChina
| | - Qiuping Wang
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina
| | - Wuxiyar Otkur
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina
| | - Haifeng Zhao
- Department of OrthopedicsDalian Second People's HospitalDalianChina
| | - Yun Lu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina
- Department of StomatologyDalian Medical UniversityDalianChina
| | - Xiaolong Liu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina
| | - Hai‐long Piao
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina
- University of Chinese Academy of SciencesBeijingChina
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23
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Yokoe H, Kiriyama A, Shimoda M, Nakajima S, Hashizume Y, Endo Y, Iwamoto R, Tsubuki M, Kanoh N. Cis-Selective Double Spirocyclization via Dearomatization and Isomerization under Thermodynamic Control. J Org Chem 2023; 88:1803-1814. [PMID: 36632764 DOI: 10.1021/acs.joc.2c02225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Spiro compounds have been considered key scaffolds for pharmaceutical applications. Although many synthetic methods exist for monospirocycles, fewer approaches are known for dispirocycles. Here, we report a highly cis-selective method for constructing a 5/6/5-dispirocyclic structure containing pyrrolidine and γ-lactam rings with various substituents from a series of N-arylpropiolamides. The high cis-selectivity would result from isomerization under thermodynamic control. Cis- and trans-diastereomers can be in equilibrium, favoring cis-adducts.
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Affiliation(s)
- Hiromasa Yokoe
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Akiko Kiriyama
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Miho Shimoda
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Satoru Nakajima
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Yuna Hashizume
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Yuto Endo
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Ryoko Iwamoto
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Masayoshi Tsubuki
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Naoki Kanoh
- School of Pharmacy and Pharmaceutical Sciences and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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24
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Merlini A, Pavese V, Manessi G, Rabino M, Tolomeo F, Aliberti S, D’Ambrosio L, Grignani G. Targeting cyclin-dependent kinases in sarcoma treatment: Current perspectives and future directions. Front Oncol 2023; 13:1095219. [PMID: 36741019 PMCID: PMC9893281 DOI: 10.3389/fonc.2023.1095219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Effective treatment of advanced/metastatic bone and soft tissue sarcomas still represents an unmet medical need. Recent advances in targeted therapies have highlighted the potential of cyclin-dependent kinases (CDK) inhibitors in several cancer types, including sarcomas. CDKs are master regulators of the cell cycle; their dysregulation is listed among the "hallmarks of cancer" and sarcomas are no exception to the rule. In this review, we report both the molecular basis, and the potential therapeutic implications for the use of CDK inhibitors in sarcoma treatment. What is more, we describe and discuss the possibility and biological rationale for combination therapies with conventional treatments, target therapy and immunotherapy, highlighting potential avenues for future research to integrate CDK inhibition in sarcoma treatment.
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Affiliation(s)
- Alessandra Merlini
- Candiolo Cancer Institute, IRCCS-FPO, Turin, Italy,Department of Oncology, University of Turin, Turin, Italy
| | - Valeria Pavese
- Department of Oncology, University of Turin, Turin, Italy
| | - Giulia Manessi
- Department of Oncology, University of Turin, Turin, Italy
| | - Martina Rabino
- Department of Oncology, University of Turin, Turin, Italy
| | | | | | - Lorenzo D’Ambrosio
- Department of Oncology, University of Turin, Turin, Italy,Medical Oncology, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy,*Correspondence: Lorenzo D’Ambrosio,
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25
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Sekiguchi N, Kasahara S, Miyamoto T, Kiguchi T, Ohno H, Takagi T, Tachibana M, Sumi H, Kakurai Y, Yamashita T, Usuki K. Phase I dose-escalation study of milademetan in patients with relapsed or refractory acute myeloid leukemia. Int J Hematol 2023; 117:68-77. [PMID: 36258088 PMCID: PMC9813109 DOI: 10.1007/s12185-022-03464-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/30/2022] [Accepted: 09/30/2022] [Indexed: 01/26/2023]
Abstract
Long-term survival in patients with acute myeloid leukemia (AML) remains low, and current treatment modalities are inadequate. Milademetan (DS-3032, RAIN-32), a small-molecule specific murine double minute 2 inhibitor, has shown a p53 status-dependent antitumor effect in vitro studies. This is the first phase I study report of milademetan monotherapy in relapsed/refractory (R/R) AML patients evaluating the safety, tolerability, pharmacokinetics, and preliminary tumor response for further clinical development. Fourteen patients received 90 (starting dose, n = 4), 120 (n = 6), or 160 mg (n = 4) of oral milademetan once daily in a 14/28 treatment cycle. The median total treatment duration was 1.5 cycles. Dose-limiting toxicity did not occur, and the maximum tolerated dose was not reached. Thus, the recommended dose was defined as 160 mg. The most common adverse events (AEs) were decreased appetite (64.3%), febrile neutropenia (50%), nausea (42.9%), and anemia (35.7%). No deaths or AEs leading to treatment discontinuation occurred. Five serious treatment-emergent AEs occurred in 4 patients. Plasma concentration increased linearly with milademetan dose. However, trends in the safety and efficacy of oral milademetan in patients with R/R AML warrant further clinical investigation. This study can inform future milademetan studies in hematologic malignancies.
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Affiliation(s)
- Naohiro Sekiguchi
- National Hospital Organization Disaster Medical Center, Tokyo, Japan
| | | | | | - Toru Kiguchi
- Dokkyo Medical University Saitama Medical Center, Saitama, Japan ,Chugoku Central Hospital, Hiroshima, Japan
| | | | | | | | | | | | | | - Kensuke Usuki
- Department of Hematology, NTT Medical Center Tokyo, 5‑9‑22 Higashi‑Gotanda, Shinagawa‑ku, Tokyo, 141‑8625 Japan
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26
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Andrysik Z, Sullivan KD, Kieft JS, Espinosa JM. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nat Commun 2022; 13:7400. [PMID: 36456590 PMCID: PMC9715646 DOI: 10.1038/s41467-022-35089-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 11/17/2022] [Indexed: 12/03/2022] Open
Abstract
The p53 transcription factor is a master regulator of cellular stress responses inhibited by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces apoptosis in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2α-ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2α, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2α phosphorylation. Pharmacological induction of eIF2α phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2α-ATF4, with clear therapeutic implications.
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Affiliation(s)
- Zdenek Andrysik
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
| | - Kelly D Sullivan
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Jeffrey S Kieft
- Department of Biochemistry and Molecular Genetics and RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Joaquin M Espinosa
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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27
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Romani A, Zauli E, Zauli G, AlMesfer S, Al-Swailem S, Voltan R. MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma. Front Oncol 2022; 12:1000677. [PMID: 36338723 PMCID: PMC9632280 DOI: 10.3389/fonc.2022.1000677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/07/2022] [Indexed: 12/04/2022] Open
Abstract
MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.
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Affiliation(s)
- Arianna Romani
- Department of Environmental and Prevention Sciences and Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Enrico Zauli
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Saleh AlMesfer
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Samar Al-Swailem
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Rebecca Voltan
- Department of Environmental and Prevention Sciences and Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA) Centre, University of Ferrara, Ferrara, Italy
- *Correspondence: Rebecca Voltan,
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28
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Zhang L, Poland B, Green M, Wong S, Slatter JG. A Population Pharmacokinetic-Pharmacodynamic Model of Navtemadlin, its Major Active Metabolite (M1) and Serum Macrophage Inhibitory Cykokine-1 (MIC-1). Xenobiotica 2022; 52:555-566. [PMID: 36052821 DOI: 10.1080/00498254.2022.2114116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Navtemadlin is a potent, selective, orally available inhibitor of murine double minute 2 that restores p53 activity to induce apoptosis in TP53 wild-type malignancies. Using richly sampled pharmacokinetic (PK) and pharmacodynamic (PD) data from healthy volunteers, a population PK/PD model was developed. A population PK (PPK) model described the PK characteristics of navtemadlin and its major metabolite acyl glucuronide (M1) and quantified enterohepatic recirculation (EHR). Post hoc individual PK parameters from this model were coupled with PD data for serum macrophage inhibitory cytokine-1 (MIC-1, GDF15), a cytokine biomarker of p53 activation, to construct a population PK/PD model that described plasma concentration-driven MIC-1 excursions and enabled simulation of the extent and duration of navtemadlin PD effects. The median apparent clearance (CL/F) and apparent central volume (V2/F) of navtemadlin were 36.4 L/hr and 159 L. The typical maximum stimulatory effect (Smax) was close to the median maximum MIC-1 ratio to baseline of 7.29 in observed data. Simulation revealed a dose-dependent increase of MIC-1 with steady state attained in approximately 7 days, in a 7-day-on/21-day-off dose regimen. Elevated MIC-1 concentrations persist through 17-19 days, leaving about 9-11 PD-free days in a 28-day cycle.
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Affiliation(s)
- Lu Zhang
- Certara Integrated Drug Development, Princeton, NJ, USA
| | - Bill Poland
- Certara Integrated Drug Development, Princeton, NJ, USA
| | | | - Shekman Wong
- Kartos Therapeutics, Inc, Redwood City, CA and Bellevue, WA USA
| | - J Greg Slatter
- Kartos Therapeutics, Inc, Redwood City, CA and Bellevue, WA USA
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29
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Zhao R, Li H, Ge W, Zhu X, Zhu L, Wan X, Wang G, Pan H, Lu J, Han W. Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations. Cancers (Basel) 2022; 14:cancers14163849. [PMID: 36010842 PMCID: PMC9405706 DOI: 10.3390/cancers14163849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/30/2022] [Accepted: 08/02/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Hepatoid adenocarcinoma of the stomach (HAS) is a subset of gastric cancer (GC) histologically characterized by hepatocellular carcinoma-like foci with or without alpha-fetoprotein secretion, which is easily misdiagnosed. Genomic alterations and potential targets for this population are still largely unknown. Additionally, treatment regimens of HAS are mainly based on GC guidelines, which is not reasonable for diseases with great heterogeneity. The present study comprehensively depicts the genomic features of HAS, and they are significantly different from GC, AFP-producing GC (AFPGC), and liver hepatocellular carcinoma (LIHC). Multiple aggressive behavior-related amplificated or deleted regions in HAS are firstly reported. Moreover, reliable and practicable clinically actionable alterations for HAS are identified, providing evidence for making personalized therapy based on the genomic characteristics of HAS instead of GC. Abstract Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignancy with aggressive biological behavior. This study aimed to compare the genetic landscape of HAS with liver hepatocellular carcinoma (LIHC), gastric cancer (GC), and AFP-producing GC (AFPGC) and identify clinically actionable alterations. Thirty-eight cases of HAS were collected for whole-exome sequencing. Significantly mutated genes were identified. TP53 was the most frequently mutated gene (66%). Hypoxia, TNF-α/NFκB, mitotic spindle assembly, DNA repair, and p53 signaling pathways mutated frequently. Mutagenesis mechanisms in HAS were associated with spontaneous or enzymatic deamination of 5-methylcytosine to thymine and defective homologous recombination-related DNA damage repair. However, LIHC was characteristic of exposure to aflatoxin and aristolochic acid. The copy number variants (CNVs) in HAS was significantly different compared to LIHC, GC, and AFPGC. Aggressive behavior-related CNVs were identified, including local vascular invasion, advanced stages, and adverse prognosis. In 55.26% of HAS patients there existed at least one clinically actionable alteration, including ERBB2, FGFR1, CDK4, EGFR, MET, and MDM2 amplifications and BRCA1/2 mutations. MDM2 amplification with functional TP53 was detected in 5% of HAS patients, which was proved sensitive to MDM2 inhibitors. A total of 10.53% of HAS patients harbored TMB > 10 muts/Mb. These findings improve our understanding of the genomic features of HAS and provide potential therapeutic targets.
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Affiliation(s)
- Rongjie Zhao
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Hongshen Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Weiting Ge
- Cancer Institute, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310005, China
| | - Xiuming Zhu
- Department of Medical Oncology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou 314408, China
| | - Liang Zhu
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou 310005, China
| | - Xiangbo Wan
- Department of Radical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 518052, China
| | - Guanglan Wang
- Department of Pathology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Jie Lu
- Department of Gastroenterology, Gongli Hospital of Shanghai Pudong New Area, Shanghai University, Shanghai 200135, China
- Department of Gastroenterology, The Tenth People’s Hospital of Tongji University, Shanghai 311202, China
- Correspondence: (J.L.); (W.H.)
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
- Correspondence: (J.L.); (W.H.)
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30
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Dedifferentiation in low-grade osteosarcoma: a Japanese Musculoskeletal Oncology Group (JMOG) study. Int J Clin Oncol 2022; 27:1758-1766. [PMID: 35932377 DOI: 10.1007/s10147-022-02223-8] [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: 04/15/2022] [Accepted: 07/16/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Low-grade osteosarcomas, namely parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LGCOS), occasionally dedifferentiate into high-grade malignancy, referred to as dedifferentiation in low-grade osteosarcoma (DLOS). This study aimed to elucidate the clinicopathologic features of DLOS, which are poorly described to date due to the extreme rarity of the disease. METHODS A total of 33 patients with DLOS were included. Clinical characteristics, including the diagnostic accuracy of tumor biopsy, multimodal treatments, and clinical course, were retrospectively reviewed. Univariate analysis was performed to identify prognostic factors associated with overall survival (OS) and metastasis-free survival (MFS). RESULTS The tumor subtypes comprised 10 cases (30.3%) of LGCOS and 23 cases (69.7%) of POS. The timing of dedifferentiation was synchronous in 25 (75.8%) and metachronous in 8 (24.2%) patients. The rates of preoperative diagnosis of DLOS were 40.0% and 65.4% for core needle biopsy and incisional biopsy, respectively. All patients underwent surgery and 25 patients received perioperative chemotherapy. Of the 13 patients who received neoadjuvant chemotherapy, 11 exhibited a poor histological response. The 5-year OS and MFS rates were 88.1% and 77.7%, respectively. Univariate analysis revealed that local recurrence was associated with poor OS (P < 0.01) and MFS (P < 0.01). Perioperative chemotherapy did not affect OS or MFS. CONCLUSIONS The diagnostic accuracy of tumor biopsy for DLOS was lower than that for bone sarcomas, as reported previously. In contrast to conventional osteosarcomas with high chemosensitivity, both histological responses and survival analysis revealed low efficacy of chemotherapy for DLOS.
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31
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Ananthapadmanabhan V, Frost TC, Soroko KM, Knott A, Magliozzi BJ, Gokhale PC, Tirunagaru VG, Doebele RC, DeCaprio JA. Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma. JCI Insight 2022; 7:e160513. [PMID: 35801592 PMCID: PMC9310528 DOI: 10.1172/jci.insight.160513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/03/2022] [Indexed: 01/13/2023] Open
Abstract
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.
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Affiliation(s)
- Varsha Ananthapadmanabhan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas C. Frost
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA
| | - Kara M. Soroko
- Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Aine Knott
- Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Brianna J. Magliozzi
- Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Prafulla C. Gokhale
- Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | | | | | - James A. DeCaprio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA
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32
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Ramharter J, Kulhanek M, Dettling M, Gmaschitz G, Karolyi-Oezguer J, Weinstabl H, Gollner A. Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis–Beirut Reaction. Org Process Res Dev 2022; 26:2526-2531. [PMID: 36032359 PMCID: PMC9396656 DOI: 10.1021/acs.oprd.2c00192] [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] [Indexed: 01/22/2023]
Abstract
![]()
Herein, we report
the structure and synthesis of the potent MDM2-p53
inhibitor BI-0282. The complex spirooxindole scaffold bearing four
stereocenters embedded in a rigid polycyclic ring-system was effectively
prepared on a multi-gram scale in only five synthesis steps employing
a three-component 1,3-dipolar cycloaddition and a late-stage Davis–Beirut
reaction as key steps.
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Affiliation(s)
- Juergen Ramharter
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
| | - Michael Kulhanek
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
| | - Maike Dettling
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
| | - Gerhard Gmaschitz
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
| | - Jale Karolyi-Oezguer
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
| | - Harald Weinstabl
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
| | - Andreas Gollner
- Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
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da Mota VHS, Freire de Melo F, de Brito BB, Silva FAFD, Teixeira KN. Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development. World J Clin Oncol 2022; 13:496-504. [PMID: 35949428 PMCID: PMC9244969 DOI: 10.5306/wjco.v13.i6.496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/16/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is known that p53 suppression is an important marker of poor prognosis of cancers, especially in solid tumors of the breast, lung, stomach, and esophagus; liposarcomas, glioblastomas, and leukemias. Because p53 has mouse double minute 2 (MDM2) as its primary negative regulator, this molecular docking study seeks to answer the following hypotheses: Is the interaction between DS-3032B and MDM2 stable enough for this drug to be considered as a promising neoplastic inhibitor? AIM To analyze, in silico, the chemical bonds between the antagonist DS-3032B and its binding site in MDM2. METHODS For molecular docking simulations, the file containing structures of MDM2 (receptor) and the drug DS-3032B (ligand) were selected. The three-dimensional structure of MDM2 was obtained from Protein Data Bank, and the one for DS-3032B was obtained from PubChem database. The location and dimensions of the Grid box was determined using AutoDock Tools software. In this case, the dimensions of the Grid encompassed the entire receptor. The ligand DS-3032B interacts with the MDM2 receptor in a physiological environment with pH 7.4; thus, to simulate more reliably, its interaction was made with the calculation for the prediction of its protonation state using the MarvinSketch® software. Both ligands, with and without the protonation, were prepared for molecular docking using the AutoDock Tools software. This software detects the torsion points of the drug and calculates the angle of the torsions. Molecular docking simulations were performed using the tools of the AutoDock platform connected to the Vina software. The analyses of the amino acid residues involved in the interactions between the receptor and the ligand as well as the twists of the ligand, atoms involved in the interactions, and type, strength, and length of the interactions were performed using the PyMol software (pymol.org/2) and Discovery Studio from BIOVIA®. RESULTS The global alignment indicated crystal structure 5SWK was more suitable for docking simulations by presenting the p53 binding site. The three-dimensional structure 5SWK for MDM2 was selected from Protein Data Bank and the three-dimensional structure of DS-3032B was selected from PubChem (Compound CID: 73297272; Milademetan). After molecular docking simulations, the most stable conformer was selected for both protonated and non-protonated DS-3032B. The interaction between MDM2 and DS-3032B occurs with high affinity; no significant difference was observed in the affinity energies between the MDM2/pronated DS-3032B (-9.9 kcal/mol) and MDM2/non-protonated DS-3032B conformers (-10.0 kcal/mol). Sixteen amino acid residues of MDM2 are involved in chemical bonds with the protonated DS-3032B; these 16 residues of MDM2 belong to the p53 biding site region and provide high affinity to interaction and stability to drug-protein complex. CONCLUSION Molecular docking indicated that DS-3032B antagonist binds to the same region of the p53 binding site in the MDM2 with high affinity and stability, and this suggests therapeutic efficiency.
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Affiliation(s)
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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34
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Wong S, Krejsa C, Lee D, Harris A, Simard E, Wang X, Allard M, Podoll T, O'Reilly T, Slatter JG. Pharmacokinetics and Macrophage Inhibitory Cytokine-1 Pharmacodynamics of the Murine Double Minute 2 Inhibitor, Navtemadlin (KRT-232) in Fed and Fasted Healthy Subjects. Clin Pharmacol Drug Dev 2022; 11:640-653. [PMID: 35172043 PMCID: PMC9306949 DOI: 10.1002/cpdd.1070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/12/2021] [Indexed: 12/19/2022]
Abstract
This single 60-mg dose, 4-period crossover study assessed the effect of food and formulation change on navtemadlin (KRT-232) pharmacokinetics (PK) and macrophage inhibitory cytokine-1 (MIC-1) pharmacodynamics. Healthy subjects (N = 30) were randomized to 3 treatment sequences, A: new tablet, fasted (reference, dosed twice); B: new tablet, 30 minutes after a high-fat meal (test 1); C: old tablet, fasted (test 2). PK/pharmacodynamic parameters were measured over 0 to 96 hours. Adverse events were mild without any discontinuations. No serious adverse events or deaths occurred. In treatment A, navtemadlin mean (coefficient of variation) maximum concentration (Cmax ) was 525 (66) ng/mL, at median time to maximum concentration (tmax ) of 2 hours. Mean (coefficient of variation) area under the plasma concentration-time curve from time 0 to time t (AUC0-t ) was 3392 (63.3) ng • h/mL, and arithmetic mean terminal half-life was 18.6 hours. Acyl glucuronide metabolite (M1)/navtemadlin AUC0-t ratio was 0.2, and urine excretion of navtemadlin was negligible. After a meal (B vs A), navtemadlin tmax was delayed by 1 hour. Geometric least squares means ratios (90%CI) for navtemadlin Cmax and AUC0-t were 102.7% (87.4-120.6) and 81.4% (76.2-86.9), respectively. Old vs new tablet fasted formulations (C vs A) had geometric least squares means ratios (90%CI) of 78.4% (72.0-85.3) for Cmax and 85.9% (80.5-91.7) for AUC0-t . MIC-1 Cmax and AUC were comparable across groups; tmax was delayed relative to navtemadlin tmax by ≈8 hours. Navtemadlin AUC0-t and MIC-1 AUC0-t correlated significantly. In conclusion, navtemadlin can be administered safely with or without food; the new formulation does not affect navtemadlin PK. The 60-mg navtemadlin dose elicited a reproducible and robust MIC-1 response that correlated well with navtemadlin exposure, indicating that murine double minute 2 target engagement leads to p53 activation.
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Affiliation(s)
- Shekman Wong
- Kartos Therapeutics, Inc, Redwood City, CA andBellevueWashingtonUSA
| | - Cecile Krejsa
- Kartos Therapeutics, Inc, Redwood City, CA andBellevueWashingtonUSA
| | - Dana Lee
- Kartos Therapeutics, Inc, Redwood City, CA andBellevueWashingtonUSA
| | - Anna Harris
- Kartos Therapeutics, Inc, Redwood City, CA andBellevueWashingtonUSA
| | | | - Xiaohui Wang
- Certara Strategic ConsultingPrincetonNew JerseyUSA
| | | | | | | | - J. Greg Slatter
- Kartos Therapeutics, Inc, Redwood City, CA andBellevueWashingtonUSA
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35
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Zhang S, Yan Z, Li Y, Gong Y, Lyu X, Lou J, Zhang D, Meng X, Zhao Y. Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells. J Med Chem 2022; 65:6207-6230. [PMID: 35420431 DOI: 10.1021/acs.jmedchem.2c00095] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding Ki values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.
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Affiliation(s)
- Shiyan Zhang
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Ziqin Yan
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Yafang Li
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu 215123, China
| | - Yang Gong
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xilin Lyu
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Jianfeng Lou
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Daizhou Zhang
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Xiangjing Meng
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Yujun Zhao
- State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.,School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.,Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
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36
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Eisenstein M. A visual guide to restoring the guardian of the genome. Nature 2022. [PMID: 35236980 DOI: 10.1038/d41586-022-00566-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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37
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Portman N, Chen J, Lim E. MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer. Front Oncol 2021; 11:777867. [PMID: 34804982 PMCID: PMC8596371 DOI: 10.3389/fonc.2021.777867] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/19/2021] [Indexed: 11/13/2022] Open
Abstract
With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2 via inhibition of MDM2 in the CDK4/6i resistance setting.
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Affiliation(s)
- Neil Portman
- Cancer Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Julia Chen
- Cancer Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Elgene Lim
- Cancer Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
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38
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Zhang X, Zhou C, Yang Y, Liu H, Wang S, Ding X, Wang H. The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling, Virtual Screening, Molecular Docking Studies, and in vitro/in vivo Biological Evaluation. ChemMedChem 2021; 17:e202100517. [PMID: 34806333 DOI: 10.1002/cmdc.202100517] [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: 07/30/2021] [Revised: 10/04/2021] [Indexed: 11/09/2022]
Abstract
Small-molecule inhibitors of MDM2 that block the MDM2-p53 protein-protein interaction have been considered as potential therapeutic agents for the treatment of cancer. Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1-5) that display significant inhibitory effects on MDM2-p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY-5 is the most active MDM2 inhibitor with an IC50 value of 14.1±2.8 nM. Moreover, WY-5 significantly up-regulate the protein level of p53 in SK-Hep-1 cells harboring wild-type p53. In vitro anticancer study reveals that WY-5 markedly inhibits the survival of SK-Hep-1 cells. In vivo anticancer study suggests that WY-5 significantly inhibits the growth of SK-Hep-1 cells-derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY-5 may be a promising candidate for the treatment of cancer harboring wild-type p53.
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Affiliation(s)
- Xuelin Zhang
- Department of Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, China
| | - Chunqiao Zhou
- Department of Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, China
| | - Yang Yang
- Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Hailin Liu
- Department of Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, China
| | - Song Wang
- Department of Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, China
| | - Xiaoli Ding
- Department of Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, China
| | - Hu Wang
- Department of Pharmacy, The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing, 401121, China
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39
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Takahashi S, Fujiwara Y, Nakano K, Shimizu T, Tomomatsu J, Koyama T, Ogura M, Tachibana M, Kakurai Y, Yamashita T, Sakajiri S, Yamamoto N. Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study. Cancer Sci 2021; 112:2361-2370. [PMID: 33686772 PMCID: PMC8177775 DOI: 10.1111/cas.14875] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/04/2021] [Accepted: 03/04/2021] [Indexed: 12/20/2022] Open
Abstract
Milademetan (DS‐3032, RAIN‐32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2‐p53 interaction. This phase I, dose‐escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28‐day cycle. Dose‐limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment‐emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose‐limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120‐mg cohort. The plasma concentrations of milademetan increased in a dose‐dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once‐daily 21/28‐day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI‐142693.
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Affiliation(s)
| | - Yutaka Fujiwara
- Department of Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan.,Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Kenji Nakano
- The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Toshio Shimizu
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | | | - Takafumi Koyama
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Mariko Ogura
- The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Masaya Tachibana
- Quantitative Clinical Pharmacology Pharmacokinetics Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Yasuyuki Kakurai
- Data Intelligence Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Tomonari Yamashita
- Oncology Medical Science Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | | | - Noboru Yamamoto
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
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40
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Yu D, Xu Z, Cheng X, Qin J. The role of miRNAs in MDMX-p53 interplay. J Evid Based Med 2021; 14:152-160. [PMID: 33988919 DOI: 10.1111/jebm.12428] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are endogenous noncoding RNAs of 19-24 nucleotides in length and are tightly related to tumorigenesis and progression. Recent studies have demonstrated that the tumor suppressor p53 and its negative controller MDMX are regulated by miRNAs in different ways. Some miRNAs directly target p53 and regulate its expression and function, whereas some miRNAs target MDMX and regulate p53's activity indirectly. The overexpression of several miRNAs can restore the activity of p53 by negatively regulating MDMX in cancer cells. Therefore, a better understanding of the miRNAs-MDMX-p53 network will put forward potential research directions for developing anticancer therapeutics. In the present review, we mainly focus on the regulatory effects of miRNAs on the MDMX-p53 interplay as well as the role of the miRNAs-MDMX-p53 network in human cancer.
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Affiliation(s)
- Dehua Yu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhiyuan Xu
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiangdong Cheng
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Jiangjiang Qin
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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