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. 2016 Sep 15;76(18):5491-500.
doi: 10.1158/0008-5472.CAN-16-0473. Epub 2016 Sep 6.

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

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

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

Eli M Wallace et al. Cancer Res. .

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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