Journal of medicinal chemistry · 2026
Discovery of Casdatifan, Part II: A Potent and Orally Bioavailable Inhibitor of Hypoxia Inducible Factor-2α.
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Mailyan Artur K, Mata Guillaume, Beatty Joel W, Drew Samuel L, Fournier Jeremy, Yu Kai, Gal Balint, Kalisiak Jaroslaw, Yan Xuelei, Tran Anh, Su Yongli, Rosen Brandon R, Jeffrey Jenna L, Hardman Clayton, Epplin Matthew, Ginn Elaine, Sun Mei, Chen Ada, Fabila Patricia, Sivick Kelsey E, Schweickert Patrick G, Piovesan Dana, Meleza Cesar, Pham Amber T, Chen Pei-Yu, Jin Lixia, Walters Matthew J, Walker Nigel P, Kwon Hyock J, Leleti Manmohan R, Powers Jay P, Lawson Kenneth V
Аннотация
Hypoxia-inducible factor 2α (HIF-2α) is recognized as a key oncogenic driver in clear cell renal cell carcinoma (ccRCC), the most prevalent type of kidney cancer. Here, we describe the discovery of a highly potent and selective tetralin-based HIF-2α inhibitor, casdatifan (61), originating from previously identified tetrahydroquinolines reported in the Part 1 companion manuscript. Casdatifan demonstrates a potentially best-in-class clinical profile. In a healthy volunteer study (NCT05117554), casdatifan exhibited a favorable pharmacokinetic profile, with an approximate 24-h half-life suitable for once-daily oral administration. Casdatifan has shown promising clinical activity in the ARC-20 ccRCC platform study, both as monotherapy and in combination with the VEGFR tyrosine kinase inhibitor (TKI) cabozantinib. Currently, casdatifan is being evaluated in a Phase 3 trial in combination with cabozantinib (NCT07011719) in patients with advanced ccRCC.