Cited by 339Cancer, Hypoxia, and MetabolismRenal cell carcinoma treatmentAngiogenesis and VEGF in Cancer

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A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

Wallace, Eli M., Rizzi, James P., Han, Guangzhou, Wehn, Paul M., Cao, Zhaodan, Du, Xinlin, Cheng, Tzuling, Czerwinski, Robert M., Dixon, Darryl D., Goggin, Barry S., Grina, Jonas A., Halfmann, Megan M., Maddie, Melissa A., Olive, Sarah R., Schlachter, Stephen T., Tan, Huiling, Wang, Bin, Wang, Keshi, Xie, Shanhai, Xu, Rui, Yang, Hanbiao, Josey, John A.·2016·Cancer Research

DOI 10.1158/0008-5472.can-16-0473

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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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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: Wallace, Eli M.
Han, Guangzhou
Wehn, Paul M.
Dixon, Darryl D.
Tan, Huiling
Wang, Bin
Wang, Keshi
Xu, Rui
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2016-09-15
Volume: 76
Issue: 18
Pages: 5491-5500
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-16-0473
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
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 › Oncology › 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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A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

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