2. Academic Validation
  3. A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

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

  • Cancer Res. 2016 Sep 15;76(18):5491-500. doi: 10.1158/0008-5472.CAN-16-0473.
Eli M Wallace 1,  James P Rizzi 2,  Guangzhou Han 2,  Paul M Wehn 2,  Zhaodan Cao 2,  Xinlin Du 2,  Tzuling Cheng 2,  Robert M Czerwinski 2,  Darryl D Dixon 2,  Barry S Goggin 2,  Jonas A Grina 2,  Megan M Halfmann 2,  Melissa A Maddie 2,  Sarah R Olive 2,  Stephen T Schlachter 2,  Huiling Tan 2,  Bin Wang 2,  Keshi Wang 2,  Shanhai Xie 2,  Rui Xu 2,  Hanbiao Yang 2,  John A Josey 2
Affiliations

Affiliations

  • 1 Peloton Therapeutics, Inc., Dallas, Texas. eli.wallace@pelotontx.com.
  • 2 Peloton Therapeutics, Inc., Dallas, Texas.
PMID: 27635045 DOI: 10.1158/0008-5472.CAN-16-0473
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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