46P AB521, a clinical-stage, potent, and selective Hypoxia-Inducible Factor (HIF)-2α inhibitor, for the treatment of renal cell carcinoma

The transcription factor hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). HIF-2α protein levels are tightly regulated post-translationally in an oxygen-dependent manner. Hypoxic conditions or aberrations in the Von-Hippel Lindau (VHL) ubiquitin ligase complex lead to HIF-2α stabilization and transcription of various pro-tumorigenic gene sets. Clinical evidence indicates that inhibition of HIF-2α is an effective strategy to mitigate tumor growth, particularly in ccRCC, a cancer that has a high prevalence of pVHL dysfunction.