This study used PT2399 in parallel with a suite of biological tools, including an HIF-2α-mutant protein shown to block PT2399 binding to the PAS-B domain, to demonstrate that PT2399 decreases HIF-dependent transcription and antiproliferative activity in an on-target HIF-2α-dependent manner through binding to the PAS-B domain, and also that the differential therapeutic sensitivity of human kidney cancer cell lines to PT2399 likely reflects differences in their HIF-2α dependence and indicates the need for predictive biomarkers (Cho et al., 2016). This evidence concerns the gene EPAS1 and kidney cancer.