9K0I

Crystal structure of FGFR4 kinase domain with 32a

This is a non-PDB format compatible entry.

Summary for 9K0I

• Entry DOI: 10.2210/pdb9k0i/pdb
• Descriptor: Fibroblast growth factor receptor 4, (2~{S})-~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]-2-cyano-3-cyclopropyl-propanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, structural protein, transferase-transferase inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36057.08

Authors

Chen, X.J.,Chen, Y.H. (deposition date: 2024-10-15, release date: 2025-10-22, Last modification date: 2026-05-06)

Primary citation

Guo, J.,Chen, X.,Li, X.,Wang, X.,Shao, M.,Song, X.,Zhang, L.,Huang, S.,Patterson, A.V.,Smaill, J.B.,Zhou, Y.,Yu, X.,Chen, Y.,Lu, X.
Optimization of Aminoindazole derivatives as highly selective covalent inhibitors for wild-type and mutant FGFR4.
Bioorg.Chem., 160:108469-108469, 2025

PubMed Abstract: The Fibroblast growth factor receptor 4 (FGFR4) has emerged as a potential oncogenic driver in hepatocellular carcinoma (HCC), primarily due to aberrations in the FGFR4-FGF19 signaling axis. Although the FGFR4-selective inhibitors have been reported, none have received approval. Further, the clinical acquired resistance caused by FGFR4 mutations has become an unmet clinical need for cancer therapy. In this study, we designed and synthesized a series of 3-amido-1H-indazole-based FGFR4 irreversible inhibitors, targeting both wild-type FGFR4 and the gatekeeper and molecular brake mutants. The representative compound, 48c, exhibited potent inhibitory activity against FGFR4 kinase (IC = 2.9 nM) and picomolar activity against FGFR4, FGFR4, and FGFR4-driven Ba/F3 cell lines (IC < 0.1, 0.3, and 0.3 nM, respectively). 48c exhibited high selectivity across a panel of 66 kinases harboring a cysteine at the hinge region, highlighting its potential as a promising therapeutic candidate for overcoming resistance in FGFR4-associated tumors.

PubMed: 40252369
DOI: 10.1016/j.bioorg.2025.108469

Experimental method

X-RAY DIFFRACTION (2.236 Å)