8KH7

Crystal structure of FGFR4 kinase domain with 8zc

8KH7 の概要

• エントリーDOI: 10.2210/pdb8kh7/pdb
• 分子名称: Fibroblast growth factor receptor 4, SULFATE ION, 1-[4-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-5-cyano-pyridin-2-yl]-3-[6-methanoyl-5-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3-(2-morpholin-4-ylethoxy)pyridin-2-yl]urea, ... (5 entities in total)
• 機能のキーワード: fgfr4 kinase domain, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35565.77

構造登録者

Lin, Q.M.,Chen, X.J.,Chen, Y.H. (登録日: 2023-08-21, 公開日: 2024-07-31, 最終更新日: 2024-11-06)

主引用文献

Yang, F.,Lin, Q.,Song, X.,Huang, H.,Chen, X.,Tan, J.,Li, Y.,Zhou, Y.,Tu, Z.,Du, H.,Zhang, Z.M.,Ortega, R.,Lin, X.,Patterson, A.V.,Smaill, J.B.,Chen, Y.,Lu, X.
Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.
J.Med.Chem., 67:2667-2689, 2024

PubMed Abstract: Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea exhibited excellent potency against FGFR4, FGFR4, and FGFR4 with IC values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4, FGFR4, and FGFR4, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

PubMed: 38348819
DOI: 10.1021/acs.jmedchem.3c01810

実験手法

X-RAY DIFFRACTION (1.52 Å)