1. Academic Validation
  2. 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. [email protected].
  • 2 Peloton Therapeutics, Inc., Dallas, Texas.
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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