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1
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Bakleh MZ, Al Haj Zen A. The Distinct Role of HIF-1α and HIF-2α in Hypoxia and Angiogenesis. Cells 2025; 14:673. [PMID: 40358197 PMCID: PMC12071368 DOI: 10.3390/cells14090673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 04/29/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Hypoxia results in a wide range of adaptive physiological responses, including metabolic reprogramming, erythropoiesis, and angiogenesis. The response to hypoxia at the cellular level is mainly regulated by hypoxia-inducible factors (HIFs): HIF1α and HIF2α isoforms. Although structurally similar and overlapping gene targets, both isoforms can exhibit distinct expression patterns and functions in some conditions of hypoxia. The interaction between these isoforms, known as the "HIF switch", determines their coordinated function under varying oxygen levels and exposure time. In angiogenesis, HIF-1α is rapidly stabilized under acute hypoxia, prompting a metabolic shift from oxidative phosphorylation to glycolysis and initiating angiogenesis by activating endothelial cells and extracellular matrix remodeling. Conversely, HIF-2α regulates cell responses to chronic hypoxia by sustaining genes critical for vascular remodeling and maturation. The current review highlights the different roles and regulatory mechanisms of HIF-1α and HIF-2α isoforms, focusing on their involvement in cell metabolism and the multi-step process of angiogenesis. Tuning the specific targeting of HIF isoforms and finding the right therapeutic window is essential to obtaining the best therapeutic effect in diseases such as cancer and vascular ischemic diseases.
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Affiliation(s)
| | - Ayman Al Haj Zen
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
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2
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Gong L, Zhang H, Liu Y, Wang X, Xia R. Interactions Between Non-Coding RNAs and HIF-1alpha in the Context of Colorectal Cancer. Biomolecules 2025; 15:510. [PMID: 40305214 PMCID: PMC12024830 DOI: 10.3390/biom15040510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/17/2025] [Accepted: 03/30/2025] [Indexed: 05/02/2025] Open
Abstract
Hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular adaptation to hypoxia, drives colorectal cancer (CRC) progression by fueling angiogenesis, metastasis, and therapy resistance. Emerging evidence delineates intricate crosstalk between non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, and circular RNAs-and HIF-1α, forming bidirectional regulatory networks that orchestrate CRC pathogenesis. By interacting with HIF-1α, these non-coding RNAs contribute to the orchestration of the aggressive hypoxic tumor microenvironment. Recent studies have evaluated the clinical potential of lncRNAs and miRNAs in the realms of non-invasive liquid biopsies and RNA-targeted therapies. This review offers a comprehensive synthesis of recent investigations into the mechanisms by which lncRNAs and miRNAs interact with HIF-1α to modulate CRC progression. Additionally, we further explore the clinical implications of ncRNA/HIF-1α crosstalk, emphasizing their potential as diagnostic biomarkers and therapeutic targets, while also spotlighting intriguing and promising areas of ncRNA research. Methods: In this study, our search strategy employed in databases such as PubMed, Web of Science, and EMBASE is as follows: we will specify search terms, including combinations of "non-coding RNA", "HIF-1α", and "colorectal cancer", along with a date range for the literature search (for example, from 2000 to 2025) to capture the most relevant and up-to-date research.
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Affiliation(s)
| | | | | | - Xianwang Wang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (L.G.); (H.Z.); (Y.L.)
| | - Ruohan Xia
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (L.G.); (H.Z.); (Y.L.)
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3
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Grigoraș A, Amalinei C. The Role of Perirenal Adipose Tissue in Carcinogenesis-From Molecular Mechanism to Therapeutic Perspectives. Cancers (Basel) 2025; 17:1077. [PMID: 40227577 PMCID: PMC11987925 DOI: 10.3390/cancers17071077] [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: 02/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 04/15/2025] Open
Abstract
Perirenal adipose tissue (PRAT) exhibits particular morphological features, with its activity being mainly related to thermogenesis. However, an expanded PRAT area seems to play a significant role in cardiovascular diseases, diabetes mellitus, and chronic kidney disease pathogenesis. Numerous studies have demonstrated that PRAT may support cancer progression and invasion, mainly in obese patients. The mechanism underlying these processes is of dysregulation of PRAT's secretion of adipokines and pro-inflammatory cytokines, such as leptin, adiponectin, chemerin, apelin, omentin-1, vistatin, nesfatin-1, and other pro-inflammatory cytokines, modulated by tumor cells. Cancer cells may also induce a metabolic reprogramming of perirenal adipocytes, leading to increased lipids and lactate transfer to the tumor microenvironment, contributing to cancer growth in a hypoxic milieu. In addition, the PRAT browning process has been specifically detected in renal cell carcinoma (RCC), being characterized by upregulated expression of brown/beige adipocytes markers (UCP1, PPAR-ɣ, c/EBPα, and PGC1α) and downregulated white fat cells markers, such as LEPTIN, SHOX2, HOXC8, and HOXC9. Considering its multifaceted role in cancer, modulation of PRAT's role in tumor progression may open new directions for oncologic therapy improvement. Considering the increasing evidence of the relationship between PRAT and tumor cells, our review aims to provide a comprehensive analysis of the perirenal adipocytes' impact on tumor progression and metastasis.
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Affiliation(s)
- Adriana Grigoraș
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Histopathology, Institute of Legal Medicine, 700455 Iasi, Romania
| | - Cornelia Amalinei
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Histopathology, Institute of Legal Medicine, 700455 Iasi, Romania
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4
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Bishop T, Ratcliffe PJ. HIF2α: the interface between oxygen-sensing systems in physiology and pathology. Physiology (Bethesda) 2025:10.1152/physiol.00043.2024. [PMID: 39946558 PMCID: PMC7617529 DOI: 10.1152/physiol.00043.2024] [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: 08/29/2024] [Accepted: 10/02/2024] [Indexed: 03/29/2025] Open
Abstract
More than 100 years after the original descriptions of altitude adaptation, it is now clear that many of these responses are mediated by a specific isoform of the transcription factor hypoxia-inducible factor (HIF-2α). Here, we review this work, including connectivity with the oxygen chemosensitive response itself, and with paraganglioma, a tumour often affecting chemosensitive tissues.
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McDermott A, Tavassoli A. Hypoxia-inducible transcription factors: architects of tumorigenesis and targets for anticancer drug discovery. Transcription 2025; 16:86-117. [PMID: 39470609 PMCID: PMC11970764 DOI: 10.1080/21541264.2024.2417475] [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: 05/21/2024] [Revised: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 10/30/2024] Open
Abstract
Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated HIF-1 and HIF-2 levels with an aggressive tumor phenotype and poor patient outcome. Despite extensive validation as a target in cancer, pharmaceutical targeting of HIFs, particularly the interaction between α and βsubunits that forms the active transcription factor, has proved challenging. Nonetheless, many indirect inhibitors of HIFs have been identified, targeting diverse parts of this pathway. Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.
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Affiliation(s)
| | - Ali Tavassoli
- School of Chemistry, University of Southampton, Southampton, UK
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6
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Diseri A, Stravodimos G, Argyriou A, Spyroulias GA, Leonidas DD, Liakos P. Expression, purification, and biophysical analysis of a part of the C-terminal domain of human hypoxia inducible factor-2α (HIF-2α). Biochem Biophys Res Commun 2024; 739:150965. [PMID: 39556935 DOI: 10.1016/j.bbrc.2024.150965] [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: 09/03/2024] [Revised: 10/24/2024] [Accepted: 11/06/2024] [Indexed: 11/20/2024]
Abstract
Hypoxia inducible factor 2α (HIF-2α) is a member of the basic helix-loop-helix(bHLH)-Per-Arnt-Sim (PAS) family of transcription factors. It is overexpressed in several cancers, associated with poor prognosis of the patients and resistance to treatment. Here, we study the residues 366-704 of the C-terminal end of human HIF-2α, which contains the N-transcriptional activation domain (NTAD), the oxygen-dependent degradation domain (ODD), and a part of the inhibitory domain (IH). An efficient protocol was developed to produce the 366-704 domain of human HIF-2α protein. Subsequently, we analyzed its biophysical characteristics using circular dichroism spectroscopy and size exclusion chromatography showing that the protein forms an antiparallel beta sheet conformation, and a computational model of the HIF-2α structure was produced. Our data offer new structural information for the unique biological properties of HIF-2α.
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Affiliation(s)
- Aikaterini Diseri
- Laboratory of Biochemistry, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - George Stravodimos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | | | | | - Demetres D Leonidas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Panagiotis Liakos
- Laboratory of Biochemistry, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece.
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Messé M, Bernhard C, Foppolo S, Thomas L, Marchand P, Herold-Mende C, Idbaih A, Kessler H, Etienne-Selloum N, Ochoa C, Tambar UK, Elati M, Laquerriere P, Entz-Werle N, Martin S, Reita D, Dontenwill M. Hypoxia-driven heterogeneous expression of α5 integrin in glioblastoma stem cells is linked to HIF-2α. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167471. [PMID: 39154793 DOI: 10.1016/j.bbadis.2024.167471] [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: 11/21/2023] [Revised: 07/27/2024] [Accepted: 08/12/2024] [Indexed: 08/20/2024]
Abstract
Despite numerous molecular targeted therapies tested in glioblastoma (GBM), no significant progress in patient survival has been achieved in the last 20 years in the overall population of GBM patients except with TTfield setup associated with the standard of care chemoradiotherapy. Therapy resistance is associated with target expression heterogeneity and plasticity between tumors and in tumor niches. We focused on α5 integrin implicated in aggressive GBM in preclinical and clinical samples. To address the characteristics of α5 integrin heterogeneity we started with patient data indicating that elevated levels of its mRNA are related to hypoxia pathways. We turned on glioma stem cells which are considered at the apex of tumor formation and recurrence but also as they localize in hypoxic niches. We demonstrated that α5 integrin expression is stem cell line dependent and is modulated positively by hypoxia in vitro. Importantly, heterogeneity of expression is conserved in in vivo stem cell-derived mice xenografts. In hypoxic niches, HIF-2α is preferentially implicated in α5 integrin expression which confers migratory capacity to GBM stem cells. Hence combining HIF-2α and α5 integrin inhibitors resulted in proliferation and migration impairment of α5 integrin expressing cells. Stabilization of HIF-2α is however not sufficient to control integrin α5 expression. Our results show that AHR (aryl hydrocarbon receptor) expression is inversely related to HIF-2α and α5 integrin expressions suggesting a functional competition between the two transcription factors. Collectively, data confirm the high heterogeneity of a GBM therapeutic target, its induction in hypoxic niches by HIF-2α and suggest a new way to attack molecularly defined GBM stem cells.
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Affiliation(s)
- Mélissa Messé
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; UMR7178 CNRS, Hubert Curien Multidisciplinary Institute, Strasbourg University, 67000 Strasbourg, France
| | - Chloé Bernhard
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France
| | - Sophie Foppolo
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France
| | - Lionel Thomas
- UMR7178 CNRS, Hubert Curien Multidisciplinary Institute, Strasbourg University, 67000 Strasbourg, France
| | - Patrice Marchand
- UMR7178 CNRS, Hubert Curien Multidisciplinary Institute, Strasbourg University, 67000 Strasbourg, France
| | - Christel Herold-Mende
- Division of Neurosurgical Research, Department of Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Ahmed Idbaih
- Sorbonne University, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, F-75013 Paris, France
| | - Horst Kessler
- Institute for Advanced Study, Department Chemie, Technical University Munich (TUM), Lichtenbergstr. 4, 85747 Garching, Germany
| | - Nelly Etienne-Selloum
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; Pharmacy department, Institut de Cancérologie Strasbourg Europe (ICANS), 67200 Strasbourg, France
| | - Charles Ochoa
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, United States
| | - Uttam K Tambar
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, United States
| | - Mohamed Elati
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille F-59000, France
| | - Patrice Laquerriere
- UMR7178 CNRS, Hubert Curien Multidisciplinary Institute, Strasbourg University, 67000 Strasbourg, France
| | - Natacha Entz-Werle
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; Pédiatrie Onco-Hématologie-Pédiatrie III, Strasbourg University Hospital, 67091 Strasbourg, France
| | - Sophie Martin
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France
| | - Damien Reita
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; Department of Cancer Molecular Genetics, Laboratory of Biochemistry and Molecular Biology, University Hospital of Strasbourg, 67200 Strasbourg, France
| | - Monique Dontenwill
- UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France.
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8
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Liao C, Hu L, Zhang Q. Von Hippel-Lindau protein signalling in clear cell renal cell carcinoma. Nat Rev Urol 2024; 21:662-675. [PMID: 38698165 DOI: 10.1038/s41585-024-00876-w] [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] [Accepted: 03/26/2024] [Indexed: 05/05/2024]
Abstract
The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel-Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.
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Affiliation(s)
- Chengheng Liao
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Lianxin Hu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Qing Zhang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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9
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Silvestrini ML, Solazzo R, Boral S, Cocco MJ, Closson JD, Masetti M, Gardner KH, Chong LT. Gating residues govern ligand unbinding kinetics from the buried cavity in HIF-2α PAS-B. Protein Sci 2024; 33:e5198. [PMID: 39467204 PMCID: PMC11516114 DOI: 10.1002/pro.5198] [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: 07/26/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/30/2024]
Abstract
While transcription factors have been generally perceived as "undruggable," an exception is the HIF-2 hypoxia-inducible transcription factor, which contains an internal cavity that is sufficiently large to accommodate a range of small-molecules, including the therapeutically used inhibitor belzutifan. Given the relatively long ligand residence times of these small molecules and the lack of any experimentally observed pathway connecting the cavity to solvent, there has been great interest in understanding how these drug ligands exit the buried receptor cavity. Here, we focus on the relevant PAS-B domain of hypoxia-inducible factor 2α (HIF-2α) and examine how one such small molecule (THS-017) exits from the buried cavity within this domain on the seconds-timescale using atomistic simulations and ZZ-exchange NMR. To enable the simulations, we applied the weighted ensemble path sampling strategy, which generates continuous pathways for a rare-event process [e.g., ligand (un)binding] with rigorous kinetics in orders of magnitude less computing time compared to conventional simulations. Results reveal the formation of an encounter complex intermediate and two distinct classes of pathways for ligand exit. Based on these pathways, we identified two pairs of conformational gating residues in the receptor: one for the major class (N288 and S304) and another for the minor class (L272 and M309). ZZ-exchange NMR validated the kinetic importance of N288 for ligand unbinding. Our results provide an ideal simulation dataset for rational manipulation of ligand unbinding kinetics.
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Affiliation(s)
| | - Riccardo Solazzo
- Department of Pharmacy and BiotechnologyAlma Mater Studiorum‐Università di BolognaBolognaItaly
| | - Soumendu Boral
- Structural Biology InitiativeCUNY Advanced Science Research CenterNew YorkNew YorkUSA
| | - Melanie J. Cocco
- Department of Pharmaceutical SciencesUniversity of California, IrvineIrvineCaliforniaUSA
- Department of Molecular Biology and BiochemistryUniversity of California, IrvineIrvineCaliforniaUSA
| | - Joseph D. Closson
- Structural Biology InitiativeCUNY Advanced Science Research CenterNew YorkNew YorkUSA
- PhD Program in BiochemistryCUNY Graduate CenterNew YorkNew YorkUSA
| | - Matteo Masetti
- Department of Pharmacy and BiotechnologyAlma Mater Studiorum‐Università di BolognaBolognaItaly
| | - Kevin H. Gardner
- Structural Biology InitiativeCUNY Advanced Science Research CenterNew YorkNew YorkUSA
- Department of Chemistry and BiochemistryCity College of New YorkNew YorkNew YorkUSA
- PhD Programs in Biochemistry, Biology, and ChemistryCUNY Graduate CenterNew YorkNew YorkUSA
| | - Lillian T. Chong
- Department of ChemistryUniversity of PittsburghPittsburghPennsylvaniaUSA
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10
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Tu R, Ma J, Chen Y, Kang Y, Ren D, Cai Z, Zhang R, Pan Y, Liu Y, Da Y, Xu Y, Yu Y, Wang D, Wang J, Dong Y, Lu X, Zhang C. USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression. Cell Death Dis 2024; 15:749. [PMID: 39406703 PMCID: PMC11482519 DOI: 10.1038/s41419-024-07136-0] [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: 05/29/2024] [Revised: 09/27/2024] [Accepted: 10/04/2024] [Indexed: 10/19/2024]
Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel Lindau (VHL) gene loss of function mutation, which leads to the accumulation of hypoxia-inducible factor 2α (HIF2α). HIF2α has been well-established as one of the major oncogenic drivers of ccRCC, however, its therapeutic targeting remains a challenge. Through an analysis of proteomic data from ccRCCs and adjacent non-tumor tissues, we herein revealed that Ubiquitin-Specific Peptidase 7 (USP7) was upregulated in tumor tissues, and its depletion by inhibitors or shRNAs caused significant suppression of tumor progression in vitro and in vivo. Mechanistically, USP7 expression is activated by the transcription factors FUBP1 and FUBP3, and it promotes tumor progression mainly by deubiquitinating and stabilizing HIF2α. Moreover, the combination of USP7 inhibitors and afatinib (an ERBB family inhibitor) coordinately induce cell death and tumor suppression. In mechanism, afatinib indirectly inhibits USP7 transcription and accelerates the degradation of HIF2α protein, and the combination of them caused a more profound suppression of HIF2α abundance. These findings reveal a FUBPs-USP7-HIF2α regulatory axis that underlies the progression of ccRCC and provides a rationale for therapeutic targeting of oncogenic HIF2α via combinational treatment of USP7 inhibitor and afatinib.
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Affiliation(s)
- Rongfu Tu
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China.
| | - Junpeng Ma
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Center for Molecular Diagnosis and Precision Medicine, 1519 Dongyue Dadao, 330209, Nanchang, China
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Department of Clinical Laboratory, 1519 Dongyue Dadao, 330209, Nanchang, China
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, 1519 DongYue Dadao, 330209, Nanchang, China
| | - Yule Chen
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710000, Xi'an, China
| | - Ye Kang
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China
| | - Doudou Ren
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China
| | - Zeqiong Cai
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China
| | - Ru Zhang
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China
| | - Yiwen Pan
- The First Affiliated Hospital of Xi'an Jiaotong University, Precision Medicine Center, 710000, Xi'an, China
| | - Yijia Liu
- The First Affiliated Hospital of Xi'an Jiaotong University, Precision Medicine Center, 710000, Xi'an, China
| | - Yanyan Da
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Center for Molecular Diagnosis and Precision Medicine, 1519 Dongyue Dadao, 330209, Nanchang, China
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Department of Clinical Laboratory, 1519 Dongyue Dadao, 330209, Nanchang, China
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, 1519 DongYue Dadao, 330209, Nanchang, China
| | - Yao Xu
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China
| | - Yahuan Yu
- Department of Nephrology, The Affiliated Hospital of Qingdao University, 266100, Qingdao, China
| | - Donghai Wang
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, 430071, Wuhan, China
| | - Jingchao Wang
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, 518055, Shenzhen, China
| | - Yang Dong
- Department of Pathology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China
| | - Xinlan Lu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, 710000, Xi'an, China
| | - Chengsheng Zhang
- The First Affiliated Hospital of Xi'an Jiaotong University, Center for Precision Cancer Medicine, MED-X Institute, 710000, Xi'an, China.
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Center for Molecular Diagnosis and Precision Medicine, 1519 Dongyue Dadao, 330209, Nanchang, China.
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Department of Clinical Laboratory, 1519 Dongyue Dadao, 330209, Nanchang, China.
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, 1519 DongYue Dadao, 330209, Nanchang, China.
- Department of Medical Genetics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 DongYue Dadao, 330209, Nanchang, China.
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11
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Natarajan V, Satalkar V, Gumbart JC, Torres M. Molecular Dynamics Reveals Altered Interactions between Belzutifan and HIF-2 with Natural Variant G323E or Proximal Phosphorylation at T324. ACS OMEGA 2024; 9:37843-37855. [PMID: 39281922 PMCID: PMC11391435 DOI: 10.1021/acsomega.4c03777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/11/2024] [Accepted: 08/16/2024] [Indexed: 09/18/2024]
Abstract
In patients with von-Hippel Lindau (VHL) disease, hypoxia-independent accumulation of HIF-2α leads to increased transcriptional activity of HIF-2α:ARNT that drives cancers such as renal cell carcinoma. Belzutifan, a recently FDA-approved drug, is designed to prevent the transcriptional activity of HIF-2α:ARNT, thereby overcoming the consequences of its unnatural accumulation in VHL-dependent cancers. Emerging evidence suggests that the naturally occurring variant G323E located in the HIF-2α drug binding pocket prevents inhibitory activity of belzutifan analogs, though the mechanism of inhibition remains unclear. Interestingly, proximal phosphorylation at neighboring T324, previously shown to regulate HIF-2 protein interactions, has also been proposed to affect HIF-2 drug binding. Here, we used molecular dynamics (MD) simulations to understand and compare the molecular-level effects of G323E and phospho-T324 (pT324) on the belzutifan bound-HIF-2α:ARNT complex. We find that both G323E and pT324 increase structural flexibility within the drug binding site and reduce the apparent binding affinity for belzutifan. Whereas the effects of G323E are concentrated in the binding pocket Fα helix within the HIF-2α PAS-B domain, pT324 decreased the belzutifan binding affinity and stabilized the HIF-2 heterodimer through an alternate mechanism involving polar interactions between the HIF-2α PAS-B and PAS-A domains. Further analysis via ensemble machine learning uncovered important and distinct interchain residue interactions modified by G323E and pT324. These findings reveal a molecular mechanism of G323E-induced drug resistance and suggest that pT324 may also affect the efficacy of HIF-2 drug binding interactions via allosteric effects.
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Affiliation(s)
- Vishva Natarajan
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Vardhan Satalkar
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - James C Gumbart
- School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Matthew Torres
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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12
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Xu X, Closson JD, Marcelino LP, Favaro DC, Silvestrini ML, Solazzo R, Chong LT, Gardner KH. Identification of small-molecule ligand-binding sites on and in the ARNT PAS-B domain. J Biol Chem 2024; 300:107606. [PMID: 39059491 PMCID: PMC11381877 DOI: 10.1016/j.jbc.2024.107606] [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: 06/11/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Transcription factors are challenging to target with small-molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include naturally ligand-regulated transcription factors, including our prior work with the hypoxia-inducible factor (HIF)-2 transcription factor, showing that small-molecule binding within an internal pocket of the HIF-2α Per-Aryl hydrocarbon Receptor Nuclear Translocator (ARNT)-Sim (PAS)-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to modulate several ARNT-mediated signaling pathways. Using solution NMR fragment screening, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the transforming acidic coiled-coil containing protein 3 transcriptional coactivator. However, these ligands have only modest binding affinities, complicating characterization of their binding sites. We address this challenge by combining NMR, molecular dynamics simulations, and ensemble docking to identify ligand-binding "hotspots" on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/transforming acidic coiled-coil containing protein 3 inhibitors, KG-548 and KG-655, bind to a β-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, while KG-548 binds exclusively to the β-sheet surface, KG-655 can additionally bind within a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. All three ligands promoted ARNT PAS-B homodimerization, albeit to varying degrees. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.
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Affiliation(s)
- Xingjian Xu
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA; PhD Program in Biochemistry, The Graduate Center, CUNY, New York, New York, USA
| | - Joseph D Closson
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA; PhD Program in Biochemistry, The Graduate Center, CUNY, New York, New York, USA
| | | | - Denize C Favaro
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA
| | - Marion L Silvestrini
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Riccardo Solazzo
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Bologna, Italy
| | - Lillian T Chong
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kevin H Gardner
- Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA; Department of Chemistry and Biochemistry, City College of New York, New York, New York, USA; PhD. Programs in Biochemistry, Chemistry and Biology, The Graduate Center, CUNY, New York, New York, USA.
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13
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Liu J, Gao Y, Zhang X. A patent review on hypoxia-inducible factor (HIF) modulators (2021-2023). Expert Opin Ther Pat 2024; 34:651-664. [PMID: 38874005 DOI: 10.1080/13543776.2024.2368739] [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: 03/06/2024] [Accepted: 06/12/2024] [Indexed: 06/15/2024]
Abstract
INTRODUCTION Hypoxia-inducible factor (HIF) is a central regulatory factor in detecting and adapting to cellular oxygen stress. Dysregulation of HIF is associated with various human diseases. Seven HIF modulators, including six prolyl hydroxylase (PHD) inhibitors and one HIF-2α inhibitor, have already been approved for the treatment of renal anemia and cancer, respectively. AREAS COVERED This review summarizes HIF modulators patented in the 2021-2023 period. This review provides an overview of HIF downregulators, including HIF-1α inhibitors, HIF-2α inhibitors, and HIF-2α degraders, as well as HIF upregulators, including PHD, FIH, and VHL inhibitors, and HIF-2α and HIF-3α agonists. EXPERT OPINION Efforts should be made to address the adverse clinical effects associated with approved HIF-modulating drugs, including PHD inhibitors and HIF-2α inhibitors. Identification of the specific buried cavity in the HIF-2α and an opened pocket in HIF-3α offer an avenue for designing novel modulators for HIF-2α or HIF-3α. Given the similarities observed in the binding cavities of HIF-2α and HIF-3α, it should be considered whether the approved HIF-2α inhibitors also inhibit HIF-3α. A comprehensive understanding of the HIF signaling pathway biology would lead to the development of novel small-molecule HIF modulators as innovative therapeutic approaches for a wide range of human diseases.
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Affiliation(s)
| | - Yinli Gao
- Jiangsu Key Laboratory of Drug Design and Optimization, and Department of Chemistry, China Pharmaceutical University, Nanjing, China
| | - Xiaojin Zhang
- Jiangsu Key Laboratory of Drug Design and Optimization, and Department of Chemistry, China Pharmaceutical University, Nanjing, China
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14
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Xu X, Closson J, Marcelino LP, Favaro DC, Silvestrini ML, Solazzo R, Chong LT, Gardner KH. Identification of Small Molecule Ligand Binding Sites On and In the ARNT PAS-B Domain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.11.03.565595. [PMID: 37961463 PMCID: PMC10635134 DOI: 10.1101/2023.11.03.565595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Transcription factors are generally challenging to target with small molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include several naturally ligand-regulated transcription factors, including our prior work with the heterodimeric HIF-2 transcription factor which showed that small molecule binding within an internal pocket of the HIF-2α PAS-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of similarly targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to simultaneously modulate several ARNT-mediated signaling pathways. Using solution NMR screening of an in-house fragment library, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the TACC3 transcriptional coactivator. However, these ligands have only modest binding affinities, complicating characterization of their binding sites. We address this challenge by combining NMR, MD simulations, and ensemble docking to identify ligand-binding 'hotspots' on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/TACC3 inhibitors, KG-548 and KG-655, bind to a β-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, while KG-548 binds exclusively to the β-sheet surface, KG-655 can additionally bind within a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. All three ligands promoted ARNT PAS-B homodimerization, albeit to varying degrees. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.
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15
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Brugarolas J, Obara G, Beckermann KE, Rini B, Lam ET, Hamilton J, Schluep T, Yi M, Wong S, Mao ZL, Gamelin E, Tannir NM. A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma. Clin Cancer Res 2024; 30:2402-2411. [PMID: 38652038 PMCID: PMC11145158 DOI: 10.1158/1078-0432.ccr-23-3029] [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: 10/03/2023] [Revised: 02/09/2024] [Accepted: 03/26/2024] [Indexed: 04/25/2024]
Abstract
PURPOSE ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. PATIENTS AND METHODS Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly. RESULTS Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia. CONCLUSIONS ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.
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Affiliation(s)
- James Brugarolas
- The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Gregory Obara
- Comprehensive Cancer Centers of Nevada, Henderson, Nevada
| | | | - Brian Rini
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Elaine T. Lam
- University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado
| | | | | | - Min Yi
- Arrowhead Pharmaceuticals, Pasadena, California
| | - So Wong
- Arrowhead Pharmaceuticals, Pasadena, California
| | | | | | - Nizar M. Tannir
- The University of Texas MD Anderson Cancer Center, Houston, Texas
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16
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Yazdani B, Sirous H, Enguita FJ, Brogi S, Wing PAC, Fassihi A. Discovery of novel direct small-molecule inhibitors targeting HIF-2α using structure-based virtual screening, molecular dynamics simulation, and MM-GBSA calculations. Mol Divers 2024; 28:1203-1224. [PMID: 37120484 DOI: 10.1007/s11030-023-10650-6] [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: 11/12/2022] [Accepted: 04/11/2023] [Indexed: 05/01/2023]
Abstract
Hypoxia-inducible factors (HIFs) are the main regulatory factors implicated in the adaptation of cancer cells to hypoxic stress, which has provoked much interest as an attractive target for the design of promising chemotherapeutic agents. Since indirect HIF inhibitors (HIFIs) lead to the occurrence of various side effects, the need of the hour is to develop direct HIFIs, physically interacting with important functional domains within the HIF protein structure. Accordingly, in the present study, it was attempted to develop an exhaustive structure-based virtual screening (VS) process coupled with molecular docking, molecular dynamic (MD) simulation, and MM-GBSA calculations for the identification of novel direct inhibitors against the HIF-2α subunit. For this purpose, a focused library of over 200,000 compounds from the NCI database was used for VS against the PAS-B domain of the target protein, HIF-2α. This domain was suggested to be a possible ligand-binding site, which is characterized by a large internal hydrophobic cavity, unique to the HIF-2α subunit. The top-ranked compounds, NSC106416, NSC217021, NSC217026, NSC215639, and NSC277811 with the best docking scores were taken up for the subsequent in silico ADME properties and PAINS filtration. The selected drug-like hits were employed for carrying out MD simulation which was followed by MM-GBSA calculations to retrieve the candidates showing the highest in silico binding affinity towards the PAS-B domain of HIF-2α. The analysis of results indicated that all molecules, except the NSC277811, fulfilled necessary drug-likeness properties. Four selected drug-like candidates, NSC106416, NSC217021, NSC217026, and NSC215639 were found to expose the stability profiles within the cavity located inside the PAS-B domain of HIF-2α over simulation time. Finally, the results of the MM-GBSA rescoring method were indicative of the highest binding affinity of NSC217026 for the binding site of the HIF-2α PAS-B domain among selected final hits. Consequently, the hit NSC217026 could serve as a promising scaffold for further optimization toward the design of direct HIF-2α inhibitors for cancer therapy.
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Affiliation(s)
- Behnaz Yazdani
- Department of Tissue Engineering, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Hajar Sirous
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.
| | - Francisco J Enguita
- Faculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal
| | - Simone Brogi
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
| | - Peter A C Wing
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Afshin Fassihi
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
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17
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Chen K, Luo L, Tu G, Yang J, Pu W, Zhu J, Xue W, Zhang R. Computer-aided discovery of novel aryl hydrocarbon receptor ligands to regulate CYP1A1 expression in inflammatory macrophages. Chem Biol Drug Des 2024; 103:e14572. [PMID: 38923686 DOI: 10.1111/cbdd.14572] [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: 04/04/2024] [Revised: 05/29/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
The environmental factor aryl hydrocarbon receptor (AhR), a key protein connecting the external environmental signals (e.g., environmental endocrine disruptor TCDD) to internal cellular processes, is involved in the activation of peripheral macrophages and inflammatory response in human body. Thus, there is widespread interest in finding compounds to anti-inflammatory response in macrophages by targeting human AhR. Here, ensemble docking based-virtual screening was first used to screen a library (~200,000 compounds) against human AhR ligand binding domain (LBD) and 25 compounds were identified as potential inhibitors. Then, 9 out of the 25 ligands were found to down-regulate the mRNA expression of CYP1A1 (a downstream gene of AhR signaling) in AhR overexpressing macrophages. The most potent compound AE-411/41415610 was selected for further study and found to reduce both mRNA and protein expressions level of CYP1A1 in mouse peritoneal macrophage. Moreover, protein chip signal pathway analysis indicated that AE-411/41415610 play a role in regulating JAK-STAT and AKT-mTOR pathways. In sum, the discovered hits with novel scaffolds provided a starting point for future design of more effective AhR-targeted lead compounds to regulate CYP1A1 expression of inflammatory peritoneal macrophages.
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Affiliation(s)
- Kerui Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Luo
- The First Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Gao Tu
- School of Pharmaceutical Sciences, Chongqing University, Chongqing, China
| | - Jingyi Yang
- School of Pharmaceutical Sciences, Chongqing University, Chongqing, China
| | - Wang Pu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junyu Zhu
- The First Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Weiwei Xue
- School of Pharmaceutical Sciences, Chongqing University, Chongqing, China
| | - Rui Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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18
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Ball A, Mohammed S, Doigneaux C, Gardner RM, Easton JW, Turner S, Essex JW, Pairaudeau G, Tavassoli A. Identification and Development of Cyclic Peptide Inhibitors of Hypoxia Inducible Factors 1 and 2 That Disrupt Hypoxia-Response Signaling in Cancer Cells. J Am Chem Soc 2024; 146:8877-8886. [PMID: 38503564 PMCID: PMC10996005 DOI: 10.1021/jacs.3c10508] [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: 09/22/2023] [Revised: 03/07/2024] [Accepted: 03/07/2024] [Indexed: 03/21/2024]
Abstract
Hypoxia inducible factor (HIF) is a heterodimeric transcription factor composed of an oxygen-regulated α subunit and a constitutively expressed β subunit that serves as the master regulator of the cellular response to low oxygen concentrations. The HIF transcription factor senses and responds to hypoxia by significantly altering transcription and reprogramming cells to enable adaptation to a hypoxic microenvironment. Given the central role played by HIF in the survival and growth of tumors in hypoxia, inhibition of this transcription factor serves as a potential therapeutic approach for treating a variety of cancers. Here, we report the identification, optimization, and characterization of a series of cyclic peptides that disrupt the function of HIF-1 and HIF-2 transcription factors by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β. These compounds are shown to bind to HIF-α and disrupt the protein-protein interaction between the α and β subunits of the transcription factor, resulting in disruption of hypoxia-response signaling by our lead molecule in several cancer cell lines.
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Affiliation(s)
- Andrew
T. Ball
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - Soran Mohammed
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - Cyrielle Doigneaux
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - Reece M. Gardner
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - James W. Easton
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - Steven Turner
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - Jonathan W. Essex
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
| | - Garry Pairaudeau
- Discovery
Sciences IMED Biotech Unit, AstraZeneca, 310 Cambridge Science Park, Milton
Road, Cambridge CB4 0WG, U.K.
| | - Ali Tavassoli
- School
of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
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19
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Chen S, Liu Y, Wang Z, Qi C, Yu Y, Xu L, Hou T, Sheng R. Identification of 3-aryl-5-methyl-isoxazole-4-carboxamide derivatives and analogs as novel HIF-2α agonists through docking-based virtual screening and structural modification. Eur J Med Chem 2024; 268:116227. [PMID: 38387335 DOI: 10.1016/j.ejmech.2024.116227] [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: 11/19/2023] [Revised: 01/25/2024] [Accepted: 02/08/2024] [Indexed: 02/24/2024]
Abstract
Hypoxia-inducible factor-2 (HIF-2) serves as the pivotal transcription factor in cellular responses to low oxygen levels, particularly concerning the regulation of erythropoietin (EPO) production. A docking-based virtual screening on crystal structures of HIF-2α inhibitors unexpectedly identified 3-phenyl-5-methyl-isoxazole-4-carboxamide derivative v19 as a hit of HIF-2α agonist. Further structural optimizations of compound v19 led to the discovery of a series of HIF-2α agonists with novel scaffolds. The most promising compounds 12g and 14d exhibited potent HIF-2α agonistic activities in vitro with EC50 values of 2.29 μM and 1.78 μM, respectively. Molecular dynamics simulations have revealed their capacity to allosterically enhance HIF-2 dimerization, which shed light on their mechanism of action. Moreover, compound 14d demonstrated a favorable pharmacokinetic (PK) profile, boasting an impressive oral bioavailability value of 68.71 %. These findings strongly suggest that compound 14d is an auspicious lead compound for the treatment of renal anemia.
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Affiliation(s)
- Siyuan Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yao Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhe Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Chengcheng Qi
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yanzhen Yu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Lei Xu
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China
| | - Tingjun Hou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Rong Sheng
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Jinhua Institute of Zhejiang University, Zhejiang University, Jinhua, 321036, China.
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20
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Xiong L, Zhang Y, Wang J, Yu M, Huang L, Hou Y, Li G, Wang L, Li Y. Novel small molecule inhibitors targeting renal cell carcinoma: Status, challenges, future directions. Eur J Med Chem 2024; 267:116158. [PMID: 38278080 DOI: 10.1016/j.ejmech.2024.116158] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/13/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Renal cell carcinoma (RCC) is the most common renal malignancy with a rapidly increasing morbidity and mortality rate gradually. RCC has a high mortality rate and an extremely poor prognosis. Despite numerous treatment strategies, RCC is resistant to conventional radiotherapy and chemotherapy. In addition, the limited clinical efficacy and inevitable resistance of multiple agents suggest an unmet clinical need. Therefore, there is an urgent need to develop novel anti-RCC candidates. Nowadays many promising results have been achieved with the development of novel small molecule inhibitors against RCC. This paper reviews the recent research progress of novel small molecule inhibitors targeting RCC. It is focusing on the structural optimization process and conformational relationships of small molecule inhibitors, as well as the potential mechanisms and anticancer activities for the treatment of RCC. To provide a theoretical basis for promoting the clinical translation of novel small molecule inhibitors, we discussed their application prospects and future development directions. It could be capable of improving the clinical efficacy of RCC and improving the therapy resistance for RCC.
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Affiliation(s)
- Lin Xiong
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Ya Zhang
- College of Life Sciences, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States
| | - Min Yu
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Liming Huang
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Yanpei Hou
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Guisen Li
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Li Wang
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Yi Li
- Department of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.
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21
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Yuan X, Ruan W, Bobrow B, Carmeliet P, Eltzschig HK. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat Rev Drug Discov 2024; 23:175-200. [PMID: 38123660 DOI: 10.1038/s41573-023-00848-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 12/23/2023]
Abstract
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
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Affiliation(s)
- Xiaoyi Yuan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Wei Ruan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Anaesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bentley Bobrow
- Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Holger K Eltzschig
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- Outcomes Research Consortium, Cleveland, OH, USA.
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22
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Zhuang J, Shang Q, Rastinejad F, Wu D. Decoding Allosteric Control in Hypoxia-Inducible Factors. J Mol Biol 2024; 436:168352. [PMID: 37935255 DOI: 10.1016/j.jmb.2023.168352] [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: 08/15/2023] [Revised: 10/10/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
The mammalian family of basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factors possess the ability to sense and respond to diverse environmental and physiological cues. These proteins all share a common structural framework, comprising a bHLH domain, two PAS domains, and transcriptional activation or repression domain. To function effectively as transcription factors, members of the family must form dimers, bringing together bHLH segments to create a functional unit that allows for DNA response element binding. The significance of bHLH-PAS family is underscored by their involvement in many major human diseases, offering potential avenues for therapeutic intervention. Notably, the clear identification of ligand-binding cavities within their PAS domains enables the development of targeted small molecules. Two examples are Belzutifan, targeting hypoxia-inducible factor (HIF)-2α, and Tapinarof, targeting the aryl hydrocarbon receptor (AHR), both of which have gained regulatory approval recently. Here, we focus on the HIF subfamily. The crystal structures of all three HIF-α proteins have been elucidated, revealing their bHLH and tandem PAS domains are used to engage their dimerization partner aryl hydrocarbon receptor nuclear translocator (ARNT, also called HIF-1β). A broad range of recent findings point to a shared allosteric modulation mechanism among these proteins, whereby small-molecules at the PAS-B domains exert direct influence over the HIF-α transcriptional functions. As our understanding of the architectural and allosteric mechanisms of bHLH-PAS proteins continues to advance, the possibility of discovering new therapeutic drugs becomes increasingly promising.
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Affiliation(s)
- Jingjing Zhuang
- Marine College, Shandong University, Weihai 264209, China; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Qinghong Shang
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Fraydoon Rastinejad
- Target Discovery Institute, Nuffield Department of Medicine Research Building, University of Oxford, Old Road Campus, Oxford OX3 7FZ, UK.
| | - Dalei Wu
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
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23
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Rojas BL, Vazquez-Rivera E, Partch CL, Bradfield CA. Dimerization Rules of Mammalian PAS Proteins. J Mol Biol 2024; 436:168406. [PMID: 38109992 PMCID: PMC10922841 DOI: 10.1016/j.jmb.2023.168406] [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: 08/09/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/20/2023]
Abstract
The PAS (PER, ARNT, SIM) protein family plays a vital role in mammalian biology and human disease. This analysis arose from an interest in the signaling mechanics by the Ah receptor (AHR) and the Ah receptor nuclear translocator (ARNT). After more than fifty years by studying this and related mammalian sensor systems, describing the role of PAS domains in signal transduction is still challenging. In this perspective, we attempt to interpret recent studies of mammalian PAS protein structure and consider how this new insight might explain how these domains are employed in human signal transduction with an eye towards developing strategies to target and engineer these molecules for a new generation of therapeutics. Our approach is to integrate our understanding of PAS protein history, cell biology, and molecular biology with recent structural discoveries to help explain the mechanics of mammalian PAS protein signaling. As a learning set, we focus on sequences and crystal structures of mammalian PAS protein dimers that can be visualized using readily available software.
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Affiliation(s)
- Brenda L Rojas
- Molecular and Environmental Toxicology Center, University of Wisconsin at Madison, USA
| | | | - Carrie L Partch
- Department of Chemistry and Biochemistry, University of California at Santa Cruz, USA
| | - Christopher A Bradfield
- Molecular and Environmental Toxicology Center, University of Wisconsin at Madison, USA; McArdle Laboratory for Cancer Research. University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA.
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24
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Khorasanizadeh S, Gardner KH. Mechanisms of PAS Domain Signalling, from Sensing Varied Small Molecules and Peptides to Approved Pharmaceuticals and Use in Optogenetics. J Mol Biol 2024; 436:168457. [PMID: 38278435 DOI: 10.1016/j.jmb.2024.168457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2024]
Affiliation(s)
| | - Kevin H Gardner
- CUNY Advanced Science Research Center, The City College of New York, USA.
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25
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Ortmann BM. Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity. BMJ ONCOLOGY 2024; 3:e000154. [PMID: 39886164 PMCID: PMC11203102 DOI: 10.1136/bmjonc-2023-000154] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 01/03/2024] [Indexed: 02/01/2025]
Abstract
Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF's dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine. Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.
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Affiliation(s)
- Brian M Ortmann
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
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26
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Golijanin B, Malshy K, Khaleel S, Lagos G, Amin A, Cheng L, Golijanin D, Mega A. Evolution of the HIF targeted therapy in clear cell renal cell carcinoma. Cancer Treat Rev 2023; 121:102645. [PMID: 37879247 DOI: 10.1016/j.ctrv.2023.102645] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 10/11/2023] [Accepted: 10/14/2023] [Indexed: 10/27/2023]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.
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Affiliation(s)
- Borivoj Golijanin
- The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.
| | - Kamil Malshy
- The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
| | - Sari Khaleel
- The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
| | - Galina Lagos
- Lifespan Cancer Institute, Department of Hematology and Oncology, The Miriam Hospital, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
| | - Ali Amin
- Department of Pathology and Laboratory Medicine, The Miriam Hospital, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, The Miriam Hospital, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
| | - Dragan Golijanin
- The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
| | - Anthony Mega
- Lifespan Cancer Institute, Department of Hematology and Oncology, The Miriam Hospital, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States
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27
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Qin Q, Nein E, Flaten A, Zhang T. Toxicity Management of Systemic Kidney Cancer Therapies. Hematol Oncol Clin North Am 2023; 37:993-1003. [PMID: 37353375 DOI: 10.1016/j.hoc.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/25/2023]
Abstract
Systemic treatments for metastatic renal cell carcinoma have expanded to include antiangiogenic agents targeting either vascular endothelial growth factor receptor, immune checkpoint inhibitors against cytotoxic T-lymphocyte antigen 4, or programmed cell death 1 pathways, and combinations of these treatments. The hypoxia inducible factor-2 inhibitors are emerging, whereas mammalian target of rapamycin (inhibitors) role is fading. To sustain optimal efficacy of these agents, potential toxicities must be recognized early and clinically managed. Here, the authors discuss the adverse events attributable to these treatments and management strategies.
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Affiliation(s)
- Qian Qin
- Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8852, USA; Harold C. Simmons Comprehensive Cancer Center
| | - Ellen Nein
- Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8852, USA
| | - Andrea Flaten
- Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8852, USA; Harold C. Simmons Comprehensive Cancer Center
| | - Tian Zhang
- Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8852, USA; Harold C. Simmons Comprehensive Cancer Center.
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28
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Shirole NH, Kaelin WG. von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology. Hematol Oncol Clin North Am 2023; 37:809-825. [PMID: 37270382 PMCID: PMC11315268 DOI: 10.1016/j.hoc.2023.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The most common form of kidney cancer is clear cell renal cell carcinoma (ccRCC). Biallelic VHL tumor suppressor gene inactivation is the usual initiating event in both hereditary (VHL Disease) and sporadic ccRCCs. The VHL protein, pVHL, earmarks the alpha subunits of the HIF transcription factor for destruction in an oxygen-dependent manner. Deregulation of HIF2 drives ccRCC pathogenesis. Drugs inhibiting the HIF2-responsive growth factor VEGF are now mainstays of ccRCC treatment. A first-in-class allosteric HIF2 inhibitor was recently approved for treating VHL Disease-associated neoplasms and appears active against sporadic ccRCC in early clinical trials.
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Affiliation(s)
- Nitin H Shirole
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | - William G Kaelin
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School; Howard Hughes Medical Institute.
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29
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Suárez C, Vieito M, Valdivia A, González M, Carles J. Selective HIF2A Inhibitors in the Management of Clear Cell Renal Cancer and Von Hippel-Lindau-Disease-Associated Tumors. Med Sci (Basel) 2023; 11:46. [PMID: 37489462 PMCID: PMC10366718 DOI: 10.3390/medsci11030046] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/14/2023] [Accepted: 06/20/2023] [Indexed: 07/26/2023] Open
Abstract
Von Hippel-Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.
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Affiliation(s)
- Cristina Suárez
- Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
| | - Maria Vieito
- Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
| | - Augusto Valdivia
- Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
| | - Macarena González
- Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
| | - Joan Carles
- Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
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30
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Zhu H, Wang X, Lu S, Ou K. Metabolic reprogramming of clear cell renal cell carcinoma. Front Endocrinol (Lausanne) 2023; 14:1195500. [PMID: 37347113 PMCID: PMC10280292 DOI: 10.3389/fendo.2023.1195500] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/16/2023] [Indexed: 06/23/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is a malignancy that exhibits metabolic reprogramming as a result of genetic mutations. This reprogramming accommodates the energy and anabolic needs of the cancer cells, leading to changes in glucose, lipid, and bio-oxidative metabolism, and in some cases, the amino acid metabolism. Recent evidence suggests that ccRCC may be classified as a metabolic disease. The metabolic alterations provide potential targets for novel therapeutic interventions or biomarkers for monitoring tumor growth and prognosis. This literature review summarized recent discoveries of metabolic alterations in ccRCC, including changes in glucose, lipid, and amino acid metabolism. The development of metabolic drugs targeting these metabolic pathways was also discussed, such as HIF-2α inhibitors, fatty acid synthase (FAS) inhibitors, glutaminase (GLS) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, and arginine depletion. Future trends in drug development are proposed, including the use of combination therapies and personalized medicine approaches. In conclusion, this review provides a comprehensive overview of the metabolic alterations in ccRCC and highlights the potential for developing new treatments for this disease.
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Affiliation(s)
- Haiyan Zhu
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xin Wang
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shihao Lu
- Orthopaedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Kongbo Ou
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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31
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Gao Z, Li Z, Li X, Xiao J, Li C. Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions. Front Cell Dev Biol 2023; 11:1161541. [PMID: 37325570 PMCID: PMC10267359 DOI: 10.3389/fcell.2023.1161541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/24/2023] [Indexed: 06/17/2023] Open
Abstract
Red blood cells (RBCs) produced in vitro have the potential to alleviate the worldwide demand for blood transfusion. Hematopoietic cell differentiation and proliferation are triggered by numerous cellular physiological processes, including low oxygen concentration (<5%). In addition, hypoxia inducible factor 2α (HIF-2α) and insulin receptor substrate 2 (IRS2) were found to be involved in the progression of erythroid differentiation. However, the function of the HIF-2α-IRS2 axis in the progression of erythropoiesis is not yet fully understood. Therefore, we used an in vitro model of erythropoiesis generated from K562 cells transduced with shEPAS1 at 5% O2 in the presence or absence of the IRS2 inhibitor NT157. We observed that erythroid differentiation was accelerated in K562 cells by hypoxia. Conversely, knockdown of EPAS1 expression reduced IRS2 expression and erythroid differentiation. Intriguingly, inhibition of IRS2 could impair the progression of hypoxia-induced erythropoiesis without affecting EPAS1 expression. These findings indicated that the EPAS1-IRS2 axis may be a crucial pathway that regulates erythropoiesis and that drugs targeting this pathway may become promising agents for promoting erythroid differentiation.
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Affiliation(s)
- Zhan Gao
- Department of Blood Transfusion, Air Force Medical Center, Beijing, China
| | - Zhicai Li
- The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Xiaowei Li
- Department of Blood Transfusion, Air Force Medical Center, Beijing, China
| | - Jun Xiao
- Department of Blood Transfusion, Air Force Medical Center, Beijing, China
| | - Cuiying Li
- Department of Blood Transfusion, Air Force Medical Center, Beijing, China
- The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
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32
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Ondrová K, Zůvalová I, Vyhlídalová B, Krasulová K, Miková E, Vrzal R, Nádvorník P, Nepal B, Kortagere S, Kopečná M, Kopečný D, Šebela M, Rastinejad F, Pu H, Soural M, Rolfes KM, Haarmann-Stemmann T, Li H, Mani S, Dvořák Z. Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice. Nat Commun 2023; 14:2728. [PMID: 37169746 PMCID: PMC10174618 DOI: 10.1038/s41467-023-38478-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/02/2023] [Indexed: 05/13/2023] Open
Abstract
The human aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is a pivotal regulator of human physiology and pathophysiology. Allosteric inhibition of AhR was previously thought to be untenable. Here, we identify carvones as noncompetitive, insurmountable antagonists of AhR and characterize the structural and functional consequences of their binding. Carvones do not displace radiolabeled ligands from binding to AhR but instead bind allosterically within the bHLH/PAS-A region of AhR. Carvones do not influence the translocation of ligand-activated AhR into the nucleus but inhibit the heterodimerization of AhR with its canonical partner ARNT and subsequent binding of AhR to the promoter of CYP1A1. As a proof of concept, we demonstrate physiologically relevant Ahr-antagonism by carvones in vivo in female mice. These substances establish the molecular basis for selective targeting of AhR regardless of the type of ligand(s) present and provide opportunities for the treatment of disease processes modified by AhR.
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Affiliation(s)
- Karolína Ondrová
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Iveta Zůvalová
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Barbora Vyhlídalová
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Kristýna Krasulová
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Eva Miková
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Petr Nádvorník
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Binod Nepal
- Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Sandhya Kortagere
- Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Martina Kopečná
- Department of Experimental Biology, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - David Kopečný
- Department of Experimental Biology, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Marek Šebela
- Department of Biochemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Fraydoon Rastinejad
- Target Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of Oxford, Oxford, UK
| | - Hua Pu
- Target Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of Oxford, Oxford, UK
| | - Miroslav Soural
- Department of Organic Chemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | | | | | - Hao Li
- Department of Medicine, Oncology, Molecular Pharmacology, and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Sridhar Mani
- Department of Medicine, Oncology, Molecular Pharmacology, and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Zdeněk Dvořák
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Olomouc, Czech Republic.
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33
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Zhuang Y, Liu K, He Q, Gu X, Jiang C, Wu J. Hypoxia signaling in cancer: Implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e203. [PMID: 36703877 PMCID: PMC9870816 DOI: 10.1002/mco2.203] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023] Open
Abstract
Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia-targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.
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Affiliation(s)
- Yan Zhuang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Kua Liu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Qinyu He
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Xiaosong Gu
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Chunping Jiang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Junhua Wu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
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Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int J Mol Sci 2023; 24:ijms24032425. [PMID: 36768744 PMCID: PMC9917195 DOI: 10.3390/ijms24032425] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
The gastrointestinal tract (GI) has a unique oxygenation profile. It should be noted that the state of hypoxia can be characteristic of both normal and pathological conditions. Hypoxia-inducible factors (HIF) play a key role in mediating the response to hypoxia, and they are tightly regulated by a group of enzymes called HIF prolyl hydroxylases (PHD). In this review, we discuss the involvement of inflammation hypoxia and signaling pathways in the pathogenesis of inflammatory bowel disease (IBD) and elaborate in detail on the role of HIF in multiple immune reactions during intestinal inflammation. We emphasize the critical influence of tissue microenvironment and highlight the existence of overlapping functions and immune responses mediated by the same molecular mechanisms. Finally, we also provide an update on the development of corresponding therapeutic approaches that would be useful for treatment or prophylaxis of inflammatory bowel disease.
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Egln1Tie2Cre Mice Exhibit Similar Therapeutic Responses to Sildenafil, Ambrisentan, and Treprostinil as Pulmonary Arterial Hypertension (PAH) Patients, Supporting Egln1Tie2Cre Mice as a Useful PAH Model. Int J Mol Sci 2023; 24:ijms24032391. [PMID: 36768713 PMCID: PMC9916894 DOI: 10.3390/ijms24032391] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/09/2023] [Accepted: 01/13/2023] [Indexed: 01/27/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. Egln1Tie2Cre mice with Tie2Cre-mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50-80% mortality from the age of 3-6 months, indicating that the Egln1Tie2Cre mice model is a long-sought-after murine PAH model. However, it is unknown if Egln1Tie2Cre mice respond to FDA-approved PAH drugs in a way similar to PAH patients. Here, we tested the therapeutic effects of the three vasodilators: sildenafil (targeting nitric oxide signaling), ambrisentan (endothelin receptor antagonist), and treprostinil (prostacyclin analog) on Egln1Tie2Cre mice. All of them attenuated right ventricular systolic pressure (RVSP) in Egln1Tie2Cre mice consistent with their role as vasodilators. However, these drugs have no beneficial effects on pulmonary arterial function. Cardiac output was also markedly improved in Egln1Tie2Cre mice by any of the drug treatments. They only partially improved RV function and reduced RV hypertrophy and pulmonary vascular remodeling as well as improving short-term survival in a drug-dependent manner. These data demonstrate that Egln1Tie2Cre mice exhibit similar responses to these drugs as PAH patients seen in clinical trials. Thus, our study provides further evidence that the Egln1Tie2Cre mouse model of severe PAH is an ideal model of PAH and is potentially useful for enabling identification of drug targets and preclinical testing of novel PAH drug candidates.
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Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based Combination Therapy. Int J Mol Sci 2023; 24:ijms24020902. [PMID: 36674417 PMCID: PMC9864911 DOI: 10.3390/ijms24020902] [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: 10/20/2022] [Revised: 12/15/2022] [Accepted: 12/15/2022] [Indexed: 01/06/2023] Open
Abstract
Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative 'druggable' targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miRS), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors. Collectively, these altered biomarkers are highly interactive and are considered master regulators of processes implicated in increased tumor angiogenesis, metastasis, drug resistance, and immune evasion. In recognition of the therapeutic potential of the indicated biomarkers, considerable efforts are underway to develop therapeutically effective and selective inhibitors of individual targets. It was demonstrated that HIFS, miRS, Nrf2, and TGF-ß are targeted by a defined dose and schedule of a specific type of selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocystein (MSC). Collectively, the demonstrated pleiotropic effects of selenium were associated with the normalization of tumor vasculature, and enhanced drug delivery and distribution to tumor tissue, resulting in enhanced efficacy of multiple chemotherapeutic drugs and biologically targeted molecules. Higher selenium doses than those used in clinical prevention trials inhibit multiple targets altered in ccRCC tumors, which could offer the potential for the development of a new and novel therapeutic modality for cancer patients with similar selenium target expression. Better understanding of the underlying mechanisms of selenium modulation of specific targets altered in ccRCC could potentially have a significant impact on the development of a more efficacious and selective mechanism-based combination for the treatment of patients with cancer.
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Badve SS, Gökmen-Polar Y. Targeting the Tumor-Tumor Microenvironment Crosstalk. Expert Opin Ther Targets 2023; 27:447-457. [PMID: 37395003 DOI: 10.1080/14728222.2023.2230362] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/23/2023] [Indexed: 07/04/2023]
Abstract
INTRODUCTION Cancer development and progression is a complex process influenced by co-evolution of the cancer cells and their microenvironment. However, traditional anti-cancer therapy is mostly targeted toward cancer cells. To improve the efficacy of cancer drugs, the complex interactions between the tumor (T) and the tumor microenvironment (TME) should be considered while developing therapeutics. AREAS COVERED The present review article will discuss the components of T-TME as well as the potential to co-target these two distinct elements. We document that these approaches have resulted in success in preventing tumor progression and metastasis, albeit in animal models in some cases. Lastly, it is important to consider the tissue context and tumor type as these could significantly modify the role of these molecules/pathways and hence the overall likelihood of response. Furthermore, we discuss the potential strategies to target the components of tumor microenvironment in anti-cancer therapy. PubMed and ClinicalTrials.gov was searched through May 2023. EXPERT OPINION The tumor-tumor microenvironment cross talk and heterogeneity are major mechanisms conferring resistance to standard of care. Better understanding of the tissue specific T-TME interactions and dual targeting has the promise of improving cancer control and clinical outcomes.
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Affiliation(s)
- Sunil S Badve
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Yesim Gökmen-Polar
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
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Nishino K, Someya K, Tsukano C, Ishikawa T, Nagao M. Synthesis of 8β-hydroxy-9(11),13-abietadien-12-one from (+)-dehydroabietylamine and its AhR ligand activity. RESULTS IN CHEMISTRY 2023. [DOI: 10.1016/j.rechem.2023.100912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
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Wang N, Hua J, Fu Y, An J, Chen X, Wang C, Zheng Y, Wang F, Ji Y, Li Q. Updated perspective of EPAS1 and the role in pulmonary hypertension. Front Cell Dev Biol 2023; 11:1125723. [PMID: 36923253 PMCID: PMC10008962 DOI: 10.3389/fcell.2023.1125723] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/14/2023] [Indexed: 03/03/2023] Open
Abstract
Pulmonary hypertension (PH) is a group of syndromes characterized by irreversible vascular remodeling and persistent elevation of pulmonary vascular resistance and pressure, leading to ultimately right heart failure and even death. Current therapeutic strategies mainly focus on symptoms alleviation by stimulating pulmonary vessel dilation. Unfortunately, the mechanism and interventional management of vascular remodeling are still yet unrevealed. Hypoxia plays a central role in the pathogenesis of PH and numerous studies have shown the relationship between PH and hypoxia-inducible factors family. EPAS1, known as hypoxia-inducible factor-2 alpha (HIF-2α), functions as a transcription factor participating in various cellular pathways. However, the detailed mechanism of EPAS1 has not been fully and systematically described. This article exhibited a comprehensive summary of EPAS1 including the molecular structure, biological function and regulatory network in PH and other relevant cardiovascular diseases, and furthermore, provided theoretical reference for the potential novel target for future PH intervention.
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Affiliation(s)
- Na Wang
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
| | - Jing Hua
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
| | - Yuhua Fu
- Department of Pulmonary and Critical Care Medicine, Central Hospital of Jiading District, Shanghai, China
| | - Jun An
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiangyu Chen
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
| | - Chuancui Wang
- Department of Pulmonary and Critical Care Medicine, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Yanghong Zheng
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
| | - Feilong Wang
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
| | - Yingqun Ji
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
| | - Qiang Li
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital Affiliated by Tongji University, Shanghai, China
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Grubb T, Maganti S, Krill-Burger JM, Fraser C, Stransky L, Radivoyevitch T, Sarosiek KA, Vazquez F, Kaelin WG, Chakraborty AA. A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer. Clin Cancer Res 2022; 28:4689-4701. [PMID: 35776130 PMCID: PMC9633392 DOI: 10.1158/1078-0432.ccr-22-0669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/07/2022] [Accepted: 06/28/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Advanced/metastatic forms of clear-cell renal cell carcinomas (ccRCC) have limited therapeutic options. Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute/Novartis combined short hairpin RNA (shRNA) dataset, and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset, we sought therapeutically actionable dependencies in kidney lineage cancers. EXPERIMENTAL DESIGN We identified preferential genetic dependencies in kidney cancer cells versus other lineages. BCL2L1, which encodes the BCL-XL antiapoptotic protein, scored as the top actionable dependency. We validated this finding using genetic and pharmacologic tools in a panel of ccRCC cell lines. Select BCL-XL-dependent (versus independent) cell lines were then transcriptionally profiled to identify biomarkers and mechanistic drivers of BCL-XL dependence. Cell-based studies (in vitro and in vivo) and clinical validations were used to address physiologic relevance. RESULTS Inactivation of BCL-XL, but not BCL-2, led to fitness defects in renal cancer cells, and sensitized them to chemotherapeutics. Transcriptomic profiling identified a "BCL-XL dependency" signature, including an elevated mesenchymal gene signature. A mesenchymal state was both necessary and sufficient to confer increased BCL-XL dependence. The "BCL-XL dependency" signature was observed in approximately 30% of human ccRCCs, which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed antitumor efficacy in vivo. CONCLUSIONS Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers. See related commentary by Wang et al., p. 4600.
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Affiliation(s)
- Treg Grubb
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Smruthi Maganti
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | | | - Cameron Fraser
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Molecular and Integrative Physiology Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Laura Stransky
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Tomas Radivoyevitch
- Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Kristopher A. Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Molecular and Integrative Physiology Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | | | - William G. Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Abhishek A. Chakraborty
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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Narayan V, Jonasch E. Systemic Therapy Development in Von Hippel-Lindau Disease: An Outsized Contribution from an Orphan Disease. Cancers (Basel) 2022; 14:5313. [PMID: 36358730 PMCID: PMC9658616 DOI: 10.3390/cancers14215313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/20/2022] [Accepted: 10/28/2022] [Indexed: 11/20/2023] Open
Abstract
Over the last several decades, an improved understanding of von Hippel-Lindau disease and its underlying biology has informed the successful development of numerous anti-cancer agents, particularly for the treatment of advanced renal cell carcinoma. Most recently, this has culminated in the first regulatory approval for a systemic therapy for VHL disease-associated neoplasms. This review will trace the clinical development of systemic therapies for VHL disease and additionally highlight anticipated challenges and opportunities for future VHL systemic therapy.
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Affiliation(s)
- Vivek Narayan
- Division of Hematology/Medical Oncology, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA 19104, USA
| | - Eric Jonasch
- Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA
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Ren X, Diao X, Zhuang J, Wu D. Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan. Mol Pharmacol 2022; 102:MOLPHARM-AR-2022-000525. [PMID: 36167425 DOI: 10.1124/molpharm.122.000525] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 08/19/2022] [Accepted: 09/07/2022] [Indexed: 11/22/2022] Open
Abstract
Hypoxia-inducible factor (HIF)-2α and its obligate heterodimerization partner aryl hydrocarbon receptor nuclear translocator (ARNT), are both members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factor family. Previous studies have identified HIF-2α as a key oncogenic driver in clear cell renal cell carcinoma (ccRCC), rendering it a promising drug target for this type of kidney cancer. Belzutifan is the first HIF-2α inhibitor approved for treating ccRCC and other cancers associated with the von Hippel-Lindau (VHL) disease. However, the detailed inhibitory mechanism of belzutifan at molecular level is still unclear. Here we obtained the crystal structure of HIF-2α-ARNT heterodimer in complex with belzutifan at 2.75 Å resolution. The complex structure shows that belzutifan binds into the PAS-B pocket of HIF-2α, and it destabilizes the dimerization of HIF-2α and ARNT through allosteric effects mainly mediated by the key residue M252 of HIF-2α near the dimer interface. We further explored the inhibitory effects of belzutifan using biochemical and functional assays. The time-resolved fluorescence energy transfer (TR-FRET)-based binding assay showed that belzutifan disrupts the dimerization of HIF-2α and ARNT with a Ki value of 20 nM. The luciferase reporter assay indicated that belzutifan can efficiently inhibit the transcriptional activity of HIF-2α with an IC50 value of 17 nM. Besides, the real-time PCR assay illustrated that belzutifan can reduce the expression of HIF-2α downstream genes in 786-O kidney cancer cells in a dose-dependent manner. Our work reveals the molecular mechanism by which belzutifan allosterically inhibits HIF-2α and provides valuable information for the subsequent drug development targeting HIF-2α. Significance Statement The bHLH-PAS family of transcription factors are an emerging group of small-molecule drug targets. Belzutifan, originally developed by Peloton Therapeutics, is the first FDA-approved drug directly binding to a bHLH-PAS protein, the hypoxia-inducible factor (HIF)-2α. Based on the protein-drug complex structure, biochemical binding assays, and functional profiling of downstream gene expression, this study reveals the regulatory mechanism of how belzutifan allosterically destabilizes HIF-2α's heterodimerization with its obligate partner protein, thus reducing their transcriptional activity that links to tumor progression.
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Affiliation(s)
- Xintong Ren
- State Key Laboratory of Microbial Technology, Shandong University, China
| | - Xiaotong Diao
- State Key Laboratory of Microbial Technology, Shandong University, China
| | | | - Dalei Wu
- State Key Laboratory of Microbial Technology, Shandong University, China
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Abstract
Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.
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Bai R, Li Y, Jian L, Yang Y, Zhao L, Wei M. The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies. Mol Cancer 2022; 21:177. [PMID: 36071472 PMCID: PMC9454207 DOI: 10.1186/s12943-022-01645-2] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 08/25/2022] [Indexed: 02/08/2023] Open
Abstract
Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.
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Affiliation(s)
- Ruixue Bai
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China.,Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China
| | - Yunong Li
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China
| | - Lingyan Jian
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China
| | - Yuehui Yang
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China. .,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China. .,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China. .,Shenyang Kangwei Medical Laboratory Analysis Co. LTD, Shenyang, 110000, People's Republic of China.
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45
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Rasmussen ES, Takahashi JS, Green CB. Time to target the circadian clock for drug discovery. Trends Biochem Sci 2022; 47:745-758. [PMID: 35577675 PMCID: PMC9378619 DOI: 10.1016/j.tibs.2022.04.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/01/2022] [Accepted: 04/18/2022] [Indexed: 11/30/2022]
Abstract
The circadian clock is an intracellular timekeeping device that drives daily rhythms in diverse and extensive processes throughout the body. The clock mechanism comprises a core transcription/translation negative feedback loop that is modulated by a complex set of additional interlocking feedback loops. Pharmacological manipulation of the clock may be valuable for treating many maladies including jet lag, shift work and related sleep disorders, various metabolic diseases, and cancer. We review recent identification of small-molecule clock modulators and discuss the biochemical features of the core clock that may be amenable to future drug discovery.
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Affiliation(s)
- Emil Sjulstok Rasmussen
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Joseph S Takahashi
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Carla B Green
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Kimura S, Takeshita N, Oyanagi T, Seki D, Jiang W, Hidaka K, Fukumoto S, Takahashi I, Takano-Yamamoto T. HIF-2α Inhibits Ameloblast Differentiation via Hey2 in Tooth Development. J Dent Res 2022; 101:1637-1644. [PMID: 35912776 DOI: 10.1177/00220345221111971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Enamel is the highly mineralized outer layer of teeth; the cells responsible for enamel formation are ameloblasts. Local hypoxia and hypoxia inducible factor (HIF) in embryonic tissues are important to promote normal organogenesis. However, hypoxic state in tooth germs and the roles of HIF in ameloblast differentiation have not been understood. The aim of this study is to clarify the role of HIF in ameloblast differentiation during tooth germ development. We found that tooth germs were under hypoxia and HIF-1α and HIF-2α were expressed in tooth germs in embryonic mice. Then, we used HIF inhibitors to evaluate the function of HIF during tooth germ development. The HIF-2α inhibitor significantly decreased the size of tooth germs in organ culture, while the HIF-1α inhibitor did not apparently affect the size of tooth germs. The HIF-2α inhibitor enhanced the expression of amelogenin, a marker of ameloblast differentiation, in the tooth germs in organ culture and rat dental epithelial SF2 cells. Moreover, we found that the HIF-2α inhibitor-stimulating amelogenin expression was regulated by hes-related family basic helix-loop-helix transcription factor with YRPW motif 2(Hey2) in SF2 cells. These findings suggest that the HIF-2α-Hey2 axis plays an important role in ameloblast differentiation during tooth germ development.
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Affiliation(s)
- S Kimura
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
| | - N Takeshita
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan.,Section of Orthodontics and Dentofacial Orthopedics, Faculty of Dental Science, Kyushu University, Fukuoka, Fukuoka, Japan
| | - T Oyanagi
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
| | - D Seki
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
| | - W Jiang
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
| | - K Hidaka
- Section of Orthodontics and Dentofacial Orthopedics, Faculty of Dental Science, Kyushu University, Fukuoka, Fukuoka, Japan
| | - S Fukumoto
- Division of Pediatric Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan.,Section of Oral Medicine for Children, Faculty of Dental Science, Kyushu University, Fukuoka, Fukuoka, Japan
| | - I Takahashi
- Section of Orthodontics and Dentofacial Orthopedics, Faculty of Dental Science, Kyushu University, Fukuoka, Fukuoka, Japan
| | - T Takano-Yamamoto
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan.,Department of Biomaterials and Bioengineering, Faculty of Dental Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Design, synthesis and in vitro antiproliferation activity of some 2-aryl and -heteroaryl benzoxazole derivatives. Future Med Chem 2022; 14:1027-1048. [PMID: 35703122 DOI: 10.4155/fmc-2022-0076] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background: Phortress produces reactive electrophilic metabolites that form DNA adducts only in sensitive tumor cells. The authors converted the 2-phenylbenzothiazole nucleus in phortress to 2-aryl and -heteroaryl benzoxazole derivatives (11 new and 14 resynthesized). All synthesized compounds were studied for antitumor activity in various cancer cells. Materials & methods: Cytotoxicity, cell morphology, flow cytometry and cell-cycle analyses of compounds were performed and more active derivatives were tested in the MCF-7 cell line. Conclusion: Methyl 2-(thiophen-2-yl)benzo[d]oxazole-6-carboxylate (BK89) has a higher effect than fluorouracil to induce apoptotic cell death (apoptosis value of 49.44%). Cell-cycle analysis shows that the compounds BK89 and methyl 2-(furan-2-yl)benzo[d]oxazole-6-carboxylate (BK82) can be used as potential cell-cycle blockers by arresting MCF-7 cells in G0/G1 phase at rates of 63% and 85%, respectively.
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Hasanov E, Pimentel I, Cruellas M, Lewis MA, Jonasch E, Balmaña J. Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects. Am Soc Clin Oncol Educ Book 2022; 42:1-17. [PMID: 35671435 DOI: 10.1200/edbk_350232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.
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Affiliation(s)
- Elshad Hasanov
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Isabel Pimentel
- Breast Cancer Unit and Hereditary Cancer Unit, Medical Oncology Department, University Hospital Vall d'Hebron, Barcelona, Spain
| | - Mara Cruellas
- Breast Cancer Unit and Hereditary Cancer Unit, Medical Oncology Department, University Hospital Vall d'Hebron, Barcelona, Spain
| | | | - Eric Jonasch
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Judith Balmaña
- Breast Cancer Unit and Hereditary Cancer Unit, Medical Oncology Department, University Hospital Vall d'Hebron, Barcelona, Spain
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He J, Li Z, Dhawan G, Zhang W, Sorochinsky AE, Butler G, Soloshonok VA, Han J. Fluorine-containing drugs approved by the FDA in 2021. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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50
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MicroRNA Expression in Clear Cell Renal Cell Carcinoma Cell Lines and Tumor Biopsies: Potential Therapeutic Targets. Int J Mol Sci 2022; 23:ijms23105604. [PMID: 35628416 PMCID: PMC9147802 DOI: 10.3390/ijms23105604] [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: 05/04/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 01/25/2023] Open
Abstract
This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines-RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL-and in the four ccRCC with sarcomatoid differentiation-RCJ41T1, RCJ41T2, RCJ41M, and UOK-127-indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.
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