Belzutifan
Welireg
HIF-2α inhibitor
Evidence Score
82
Directly binds and inhibits HIF-2α, preventing its dimerization with HIF-1β (ARNT) and blocking transcription of HIF-2α target genes including VEGF, EPO, and metabolic enzymes. FDA-approved for VHL disease, which shares the same pseudohypoxic mechanism as SDH-deficient tumors.
Succinate accumulation inhibits PHD enzymes, stabilizing HIF-1α and HIF-2α regardless of oxygen levels. This drives angiogenesis (VEGF), metabolic reprogramming (glycolysis shift), and growth factor signaling.
Upstream event:
Succinate inhibits PHD1/2/3 (α-KG-dependent dioxygenases)
Downstream effects:
EPAS1
Hypoxia-inducible factor 2-alpha (HIF-2α)
HIF-2α is the primary therapeutic target in pseudohypoxic tumors. Belzutifan (MK-6482) directly inhibits HIF-2α.
UniProt: Q99814
Approved Indications
- VHL-associated renal cell carcinoma
- VHL-associated CNS hemangioblastomas
- VHL-associated pancreatic neuroendocrine tumors
Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.
Coming in Phase 3
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.