Endothelial PAS domain-containing protein 1 (HIF-2α) (HIF-2α)

Hypoxia-inducible factor 2-alpha (HIF-2α), encoded by the EPAS1 gene, is a transcription factor essential for the cellular response to low oxygen levels [1]. In healthy cells, HIF-2α is targeted for degradation by the Von Hippel-Lindau (VHL) protein; however, in clear cell renal cell carcinoma (ccRCC), VHL loss leads to the constitutive stabilization of HIF-2α, driving oncogenesis [2]. To function, HIF-2α must translocate to the nucleus and form a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT) via its PAS-B domain [4]. This interface has become a high-value therapeutic target because the PAS-B domain contains a unique internal hydrophobic cavity [2, 4]. Small-molecule inhibitors like belzutifan bind to this pocket, inducing a conformational change that allosterically disrupts the HIF-2α/ARNT interaction [3, 5]. By preventing heterodimerization, these drugs block the transcription of genes involved in angiogenesis, cell proliferation, and erythropoiesis [3]. This target is clinically validated for treating VHL-associated tumors and advanced renal cell carcinoma [3, 5]. The specificity of the PAS-B pocket allows for selective inhibition of HIF-2α over the closely related HIF-1α, minimizing off-target effects [2, 4].

Other names

EPAS1Hypoxia-inducible factor 2-alphaHIF2APASD2MOP2Member of PAS protein 2

Allosteric inhibition of HIF-2α/ARNT heterodimerization by binding to a hydrophobic pocket within the HIF-2α PAS-B domain [2, 4]