Hypoxia-inducible factor 2-alpha (HIF-2α) (HIF-2α)

Hypoxia-inducible factor 2-alpha (HIF-2α), also known as EPAS1, is a transcription factor that plays a central role in the cellular response to low oxygen levels [UniProt: P70481]. It functions as a heterodimer with HIF-1β (ARNT) to regulate the expression of genes involved in erythropoiesis, angiogenesis, and iron metabolism [PubMed: 27595394]. The PAS-B domain of HIF-2α contains a unique internal hydrophobic cavity that is absent in the closely related HIF-1α isoform, making it a highly selective target for small-molecule inhibitors [Nature: 10.1038/nature19796]. In clear cell renal cell carcinoma (ccRCC) and Von Hippel-Lindau (VHL) disease, the loss of the VHL protein leads to the constitutive stabilization and accumulation of HIF-2α, which drives tumor growth [NEJM: 385:2036-2046]. Drugs such as belzutifan (Welireg) bind specifically within the PAS-B domain pocket, inducing an allosteric change that prevents HIF-2α from dimerizing with HIF-1β [FDA: Welireg Prescribing Information]. This disruption blocks the transcription of pro-tumorigenic factors like VEGF and EPO, effectively inhibiting tumor proliferation and vascularization [Cancer Discovery: 10.1158/2159-8290.CD-16-0468]. Targeting the PAS-B domain has proven to be a successful therapeutic strategy for patients with VHL-associated tumors and advanced renal cell carcinoma [Journal of Clinical Oncology: 10.1200/JCO.21.00012].

Other names

Endothelial PAS domain-containing protein 1EPAS1HIF2APASD2MOP2HIF-2-alpha

Allosteric inhibition of HIF-2α/HIF-1β heterodimerization by binding to the PAS-B domain hydrophobic pocket, preventing transcriptional activation of hypoxia-responsive genes.