7YC1

Crystal structure of FGFR4 kinase domain with 10d

Summary for 7YC1

• Entry DOI: 10.2210/pdb7yc1/pdb
• Descriptor: Fibroblast growth factor receptor 4, ~{N}-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-5-methanoyl-1-propyl-pyrrolo[3,2-b]pyridine-3-carboxamide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, structural protein, transferase-transferase inhibitor complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35481.78

Authors

Chen, X.J.,Lin, Q.M.,Chen, Y.H. (deposition date: 2022-06-30, release date: 2022-11-16, Last modification date: 2024-10-16)

Primary citation

Yang, F.,Chen, X.,Song, X.,Ortega, R.,Lin, X.,Deng, W.,Guo, J.,Tu, Z.,Patterson, A.V.,Smaill, J.B.,Chen, Y.,Lu, X.
Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2- b ]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors.
J.Med.Chem., 65:14809-14831, 2022

PubMed Abstract: The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2-]pyridine derivatives as new reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase. The representative compound exhibited single-digit nanomolar activity against wild-type FGFR4 and the FGFR4 mutant variants in biochemical and Ba/F3 cellular assays, while sparing FGFR1/2/3. Furthermore, showed significant antiproliferative activity against Hep3B, JHH-7, and HuH-7 HCC cells with IC values of 37, 32, and 94 nM, respectively. MALDI-TOF-MS and X-ray protein crystallography studies were consistent with acting as a reversible-covalent inhibitor of FGFR4, serving as a promising lead compound for further anticancer drug development.

PubMed: 36278929
DOI: 10.1021/acs.jmedchem.2c01319

Experimental method

X-RAY DIFFRACTION (2.535 Å)