Belzutifan

Belzutifan (CAS 1672668-24-4, also known as PT2977) is a highly selective inhibitor of hypoxia-inducible factor 2α (HIF-2α), with its primary molecular target being HIF-2α. This protein is aberrantly accumulated in clear cell renal cell carcinoma (ccRCC) as a consequence of von Hippel-Lindau (VHL) gene deficiency, and serves as a key oncogenic driver in this context. The mechanism of action of Belzutifan involves binding to the PAS-B domain of HIF-2α, thereby disrupting the dimerization of HIF-2α with the aryl hydrocarbon receptor nuclear translocator (ARNT). This disruption blocks the transcriptional activation of downstream genes associated with angiogenesis, cell proliferation, and immune evasion.

In terms of bioactivity, Belzutifan demonstrates a 2- to 3-fold increase in in vitro potency compared to the first-generation inhibitor PT2385, with a significantly reduced EC85 after adjustment for free drug fraction. In preclinical mouse xenograft models, Belzutifan induces tumor regression with in vivo activity approximately ten times greater than that of PT2385. Phase I clinical studies have shown that Belzutifan exhibits stable exposure with minimal inter-individual variability; a once-daily dose of 120 mg achieves therapeutically effective plasma concentrations. In patients with advanced ccRCC, Belzutifan achieved a confirmed partial response rate of 22%, and the median progression-free survival (PFS) had not yet been reached at a median follow-up of 9 months, indicating promising clinical therapeutic potential.

References:

[1] Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, Wang B, Wehn PM, Yang H, Dixon DD, Czerwinski RM, Du X, Ged EL, Han G, Tan H, Wong T, Xie S, Josey JA, Wallace EM. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma. J Med Chem. 2019 Aug 8;62(15):6876-6893. doi: 10.1021/acs.jmedchem.9b00719. Epub 2019 Jul 8. PMID: 31282155.