9I64

Crystal structure of Casdatifan bound to HIF2a-B*:ARNT-B* complex

This is a non-PDB format compatible entry.

Summary for 9I64

• Entry DOI: 10.2210/pdb9i64/pdb
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, (5~{R},6~{S},8~{R})-3,5,6-tris(fluoranyl)-8-[(1~{S},2~{R})-2-fluoranyl-7-methylsulfonyl-1-oxidanyl-2,3-dihydro-1~{H}-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile, ... (6 entities in total)
• Functional Keywords: hif-2a inhibitor, casdatifan, ab521, clear cell renal cell carcinoma (ccrcc), hypoxia, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 27199.85

Authors

Walker, N.P.,Lawson, K.V. (deposition date: 2025-01-29, release date: 2026-02-18, Last modification date: 2026-06-17)

Primary citation

Mailyan, A.K.,Mata, G.,Beatty, J.W.,Drew, S.L.,Fournier, J.,Yu, K.,Gal, B.,Kalisiak, J.,Yan, X.,Tran, A.,Su, Y.,Rosen, B.R.,Jeffrey, J.L.,Hardman, C.,Epplin, M.,Ginn, E.,Sun, M.,Chen, A.,Fabila, P.,Sivick, K.E.,Schweickert, P.G.,Piovesan, D.,Meleza, C.,Pham, A.T.,Chen, P.Y.,Jin, L.,Walters, M.J.,Walker, N.P.,Kwon, H.J.,Leleti, M.R.,Powers, J.P.,Lawson, K.V.
Discovery of Casdatifan, Part II: A Potent and Orally Bioavailable Inhibitor of Hypoxia Inducible Factor-2 alpha.
J.Med.Chem., 2026

PubMed Abstract: 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 (), 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.

PubMed: 42246926
DOI: 10.1021/acs.jmedchem.5c03724

Experimental method

X-RAY DIFFRACTION (1.558 Å)