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Publication Abstract from PubMed

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, HIF1alpha and HIF2alpha, 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 HIF2alpha that allosterically blocks its dimerization with the HIF1alpha/2alpha transcriptional dimerization partner ARNT/HIF1beta. PT2385 inhibited the expression of HIF2alpha-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 HIF2alpha 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. (c)2016 AACR.

A Small-Molecule Antagonist of HIF2alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.,Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z, Du X, Cheng T, Czerwinski RM, Dixon DD, Goggin BS, Grina JA, Halfmann MM, Maddie MA, Olive SR, Schlachter ST, Tan H, Wang B, Wang K, Xie S, Xu R, Yang H, Josey JA Cancer Res. 2016 Sep 15;76(18):5491-500. doi: 10.1158/0008-5472.CAN-16-0473. Epub, 2016 Sep 6. PMID:27635045^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.