Discovery of Casdatifan, Part II: A Potent and Orally Bioavailable Inhibitor of Hypoxia Inducible Factor-2α

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.