6JPE

Crystal structure of FGFR4 kinase domain with irreversible inhibitor 1

6JPE の概要

• エントリーDOI: 10.2210/pdb6jpe/pdb
• 分子名称: Fibroblast growth factor receptor 4, N-[2-[[6-[2-[[2,6-bis(chloranyl)-3,5-dimethoxy-phenyl]amino]pyridin-3-yl]pyrimidin-4-yl]amino]-3-methyl-phenyl]prop-2-enamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: fgfr4, irreversible inhibitor, transferase-transferase inhibitor complex, transferase/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: 35406.54

構造登録者

Chen, X.,Dai, S.,Zhou, Z.,Chen, Y. (登録日: 2019-03-26, 公開日: 2020-05-06, 最終更新日: 2024-10-23)

主引用文献

Rezende Miranda, R.,Fu, Y.,Chen, X.,Perino, J.,Cao, P.,Carpten, J.,Chen, Y.,Zhang, C.
Development of a Potent and Specific FGFR4 Inhibitor for the Treatment of Hepatocellular Carcinoma.
J.Med.Chem., 63:11484-11497, 2020

PubMed Abstract: Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.

PubMed: 33030342
DOI: 10.1021/acs.jmedchem.0c00044

実験手法

X-RAY DIFFRACTION (1.601 Å)