Pt2385: First-In-Class Hif-2 Alpha Antagonist For The Treatment Of Renal Cell Carcinoma

Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, are transcription factors that mediate cellular response to changes of oxygen supply. These proteins become stabilized under hypoxia and subsequently activate the expression of genes to facilitate cell survival and proliferation. HIF proteins are activated in many types of cancers due to the tumor hypoxic microenvironment and have been implicated in cancer initiation, progression and metastasis. The oncogenic role of HIF-2α is pertinent in clear cell renal carcinoma (ccRCC). In the majority of ccRCC tumors, the von Hippel-Lindau protein (VHL) that targets HIF-2α for degradation is inactivated, leading to the accumulation of HIF-2α and the activation of genes that drive kidney cancer tumorigenesis. We have identified small molecules that bind to the PAS-B domain of HIF-2α protein and block it9s dimerization with ARNT (aryl hydrocarbon receptor nuclear translocator, HIF-1β), a prerequisite for its transcriptional activities. Specifically, we describe PT2385, a selective, orally active HIF-2α antagonist with potent anti-cancer activity in mouse models of ccRCC. PT2385 is currently under evaluation in Phase I clinical trials for the treatment of ccRCC. Citation Format: Eli M. Wallace, Zhaodan Cao, Tzuling Cheng, Robert Czerwinski, Darryl D. Dixon, Xinlin Du, Barry Goggin, Jonas Grina, Megan Halfmann, Guangzhou Han, Heli Huang, John A. Josey, Melissa A. Maddie, Sarah Olive, James Rizzi, Stephen T. Schlachter, Hui-Ling Tan, Bin Wang, Keshi Wang, Paul M. Wehn, Shanhai Xie, Rui Xu, Hanbiao Yang. PT2385: First-in-class HIF-2α antagonist for the treatment of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2015-DDT01-01