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


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.

DOI: 10.1158/0008-5472.CAN-16-0473

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@article{Wallace2016ASA, title={A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma.}, author={Eli M Wallace and James P. Rizzi and Guangzhou Han and Paul M Wehn and Zhaodan Cao and Xinlin Du and Tzuling Cheng and Robert M Czerwinski and Darryl D. Dixon and Barry S. Goggin and Jonas A. Grina and Megan M Halfmann and Melissa A. Maddie and Sarah R Olive and Stephen T Schlachter and Huiling Tan and Bin Wang and Keshi Wang and Shanhai Xie and Rui Xu and Hanbiao Yang and John A Josey}, journal={Cancer research}, year={2016}, volume={76 18}, pages={5491-500} }