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Belzutifan

Welireg

HIF-2α inhibitor

Evidence Score

82

established
Mechanism of Action

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.

Pathway Connections
Pseudohypoxia / HIF Pathway

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:

HIF-1α/2α stabilizationVEGF upregulationGLUT1/3 upregulationGlycolytic enzyme inductionEPO production
Molecular Targets

EPAS1

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

direct

HIF-2α is the primary therapeutic target in pseudohypoxic tumors. Belzutifan (MK-6482) directly inhibits HIF-2α.

UniProt: Q99814

Quick Facts
FDA Approved

Approved Indications

  • VHL-associated renal cell carcinoma
  • VHL-associated CNS hemangioblastomas
  • VHL-associated pancreatic neuroendocrine tumors
ChEMBL IDCHEMBL4594382
PubChem CID134816052
Evidence

Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.

Coming in Phase 3

For research exploration only — not medical advice. Consult your doctor before acting on any information.

AI Analysis

Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.