A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
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Abstract
More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.
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PT2385 and PT2977 selectively block dimerization of HIF-2α with HIF-1β.
“Recently, compounds designated PT2385 and PT2977 were shown to selectively block dimerization of HIF-2α with HIF-1β (44)”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [44]
Belzutifan and its predecessor PT2385 bind to a hydrophobic cavity within the PAS-B domain of HIF-2α, allosterically preventing heterodimerization with HIF-1β and formation of a transcriptionally active complex.
“Belzutifan and its predecessor PT2385 bind to a hydrophobic cavity within the PAS-B domain of HIF-2α, allosterically preventing heterodimerization with HIF-1β and formation of a transcriptionally active complex [410].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [410]
HIF-2α can be targeted by selective inhibitors, and these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC.
“Indeed, recent studies have shown that HIF-2α can be targeted by selective inhibitors and have indicated that these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC79–82.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [80]
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“For comparison, we tested the effect of PT2385, which inhibited EPO, NDRG1, ANGPTL4, and VEGFA expression but had no effect on CA9, which is consistent with its HIF-2–selective mechanism of action (44).”
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- Authors
- Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., Cheng, T., Czerwinski, R. M., Dixon, D. D., Goggin, B. S., Grina, J. A., Halfmann, M. M., Maddie, M. A., Olive, S. R., Schlachter, S. T., Tan, H., Wang, B., Wang, K., Xie, S., Xu, R., Yang, H., & Josey, J. A.
- Affiliations
- Peloton Therapeutics, Inc., Dallas, Texas.
- Corresponding author
- Wallace, Eli M.
- ORCID
- Venue
- Cancer Research
- Published
- 2016-09-15
- Volume
- 76
- Issue
- 18
- Pages
- 5491-5500
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2514212469
- Cited by
- 336
- References
- 40
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 38 · 2023: 36 · 2022: 25 · 2021: 37 · 2020: 41 · 2019: 38 · 2018: 30 · 2017: 22 · 2016: 7 · 2015: 1
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-2α, PT2385, clear cell renal cell carcinoma, small molecule inhibitors, hypoxia-inducible factor, VEGF-A, plasminogen activator inhibitor-1, cyclin D1, tumor xenografts, oral anticancer therapy, cardiovascular safety
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Antineoplastic Agents, Calorimetry, Carcinoma, Renal Cell, Humans, Immunohistochemistry, Kidney Neoplasms, Polymerase Chain Reaction, Mice, SCID, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Cell Line, Tumor, Immunoprecipitation, Mice, Basic Helix-Loop-Helix Proteins
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