PT2399 is a potent and orally available antagonist of HIF-2 that selectively disrupts the heterodimerization of HIF-2α with HIF-1β.
PT2399 dissociates HIF-2 (an obligatory heterodimer [HIF-2α/HIF-1β])14 in human Clear cell Renal Cell Carcinoma (ccRCC) suppressing tumorigenesis in 56% (10/18) lines. PT2399 has greater activity than sunitinib, is active in sunitinib-progressing tumors, and is better tolerated. Illustrating drug specificity, gene expression is largely unaffected by PT2399 in resistant tumors. Sensitive tumors exhibits a distinguishing gene expression signature, and generally higher HIF-2α levels. Prolonged PT2399 treatment leads to resistance.[2]
[1] Olga Martínez-Sáez, et al. Crit Rev Oncol Hematol. 2017 Mar;111:117-123. [2] Wenfang Chen, et al. Nature. 2016 Nov 3;539(7627):112-117.