belzutifan

Overview

Belzutifan (PT2977/MK-6482) is a small-molecule inhibitor of hypoxia-inducible factor 2-alpha (EPAS1), the oncogenic HIFα isoform stabilized by loss of the VHL ubiquitin ligase in clear cell renal cell carcinoma (CCRCC). By blocking HIF2A’s interaction with its obligate dimerization partner ARNT, belzutifan prevents transcription of HIF2A-regulated genes involved in tumor growth, angiogenesis, and dedifferentiation of proximal tubular cells.

Evidence in the corpus

• scRNA-seq of 147,045 mouse renal tubular cells across Vhl-knockout genotypes showed that EPAS1 (HIF2A) drives a late, time-dependent dedifferentiation of proximal tubular cells that is distinct from the early glycolytic program controlled by HIF1A; these findings support early therapeutic use of belzutifan in VHL disease to prevent expansion of Vhl-null cancer precursor cells before morphological transformation PMID:23797736.

Resistance mechanisms

• No resistance mechanisms to belzutifan are reported in the current corpus.

Cancer types (linked)

• CCRCC — VHL disease-associated and sporadic clear cell renal cell carcinoma; the primary clinical context for HIF2A inhibition.

Sources

• PMID:23797736 — Lima et al.; mouse scRNA-seq isoform dissection of HIF1A vs HIF2A in Vhl-null renal tubular epithelium; provides mechanistic rationale for early belzutifan use in VHL disease.

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