6V9C

Crystal structure of FGFR4 kinase domain in complex with covalent inhibitor

6V9C の概要

• エントリーDOI: 10.2210/pdb6v9c/pdb
• 分子名称: Fibroblast growth factor receptor 4, N-[(3R,4S)-4-{[6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}oxolan-3-yl]prop-2-enamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: tyrosine kinase inhibitor, covalent inhibitor, fgfr, kinase, 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: 34579.70

構造登録者

Liu, J.,Liu, H. (登録日: 2019-12-13, 公開日: 2020-03-25, 最終更新日: 2024-11-20)

主引用文献

Liu, H.,Niu, D.,Tham Sjin, R.T.,Dubrovskiy, A.,Zhu, Z.,McDonald, J.J.,Fahnoe, K.,Wang, Z.,Munson, M.,Scholte, A.,Barrague, M.,Fitzgerald, M.,Liu, J.,Kothe, M.,Sun, F.,Murtie, J.,Ge, J.,Rocnik, J.,Harvey, D.,Ospina, B.,Perron, K.,Zheng, G.,Shehu, E.,D'Agostino, L.A.
Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.
Acs Med.Chem.Lett., 11:1899-1904, 2020

PubMed Abstract: Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-]pyrimidin-7(8)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC.

PubMed: 33062171
DOI: 10.1021/acsmedchemlett.9b00601

実験手法

X-RAY DIFFRACTION (1.9 Å)