Belzutifan

Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor which aids in oxygen sensing by regulating genes that promote adaptation to hypoxia. In healthy patients, when oxygen levels are normal, HIF-2α is broken down via ubiquitin-proteasomal degradation by von-Hippel Lindau (VHL) proteins. In the presence of hypoxia, HIF-2α translocates into cell nuclei and forms a transcriptional complex with hypoxia-inducible factor 1β (HIF-1β) - this complex then induces the expression of downstream genes associated with cellular proliferation and angiogenesis.

Patients with von-Hippel Lindau (VHL) disease lack functional VHL proteins, leading to an accumulation of HIF-2α, and this accumulation is what drives the growth of VHL-associated tumors. Belzutifan is an inhibitor of HIF-2α that prevents its complexation with HIF-1β in conditions of hypoxia or impaired VHL protein function, thereby reducing the expression of HIF-2α target genes and slowing/stopping the growth of VHL-associated tumors.