ISDA: 9I64

Deposition Date 2025-01-29

Release Date 2026-02-18

Last Version Date 2026-07-08

Entry Detail

PDB ID:

9I64

Keywords:

TRANSCRIPTION

Title:

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

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

1.56 Å

R-Value Free:

0.21

R-Value Work:

0.19

Space Group:

P 21 21 21

Download Validation Report

Macromolecular Entities

Structures with similar UniProt ID

Structural Superimposition Protein Blast

Polymer Type:polypeptide(L)
Molecule:Endothelial PAS domain-contai
Gene (Uniprot):EPAS1
Chain IDs:A
Chain Length:112
Number of Molecules:1
Biological Source:Homo sapiens

UniProt ID:Q99814 Pfam ID:PF14598

Structures with similar UniProt ID

Structural Superimposition Protein Blast

Polymer Type:polypeptide(L)
Molecule:Aryl hydrocarbon receptor nuc
Gene (Uniprot):ARNT
Chain IDs:B
Chain Length:116
Number of Molecules:1
Biological Source:Homo sapiens

UniProt ID:P27540 Pfam ID:PF14598

Ligand Molecules

A1I0H

FMT

Primary Citation

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

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.Show

J.Med.Chem. 69 14952 14988 (2026)

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

Abstact

Hypoxia-inducible factor 2alpha (HIF-2alpha) 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-2alpha 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.

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Disease

Primary Citation of related structures

Abstact

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