7YBO

Crystal structure of FGFR4 kinase domain with 10z

7YBO の概要

• エントリーDOI: 10.2210/pdb7ybo/pdb
• 分子名称: Fibroblast growth factor receptor 4, ~{N}-[4-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-5-cyano-pyridin-2-yl]-6-bromanyl-5-(hydroxymethyl)-1-(2-morpholin-4-ylethyl)pyrrolo[3,2-b]pyridine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, inhibitor, structural protein, transferase-transferase inhibitor complex, 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: 35944.78

構造登録者

Chen, X.J.,Lin, Q.M.,Chen, Y.H. (登録日: 2022-06-29, 公開日: 2022-11-16, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.307 Å)