7DTZ

FGFR4 complex with a covalent inhibitor

7DTZ の概要

• エントリーDOI: 10.2210/pdb7dtz/pdb
• 分子名称: Fibroblast growth factor receptor 4, N-[2-[[5-[[2,6-bis(chloranyl)-3,5-dimethoxy-phenyl]methoxy]pyrimidin-2-yl]amino]-3-methyl-phenyl]-2-fluoranyl-prop-2-enamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, covalent, crystal, transferase
• 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: 35112.23

構造登録者

Chen, X.J.,Dai, S.Y.,Chen, Y.H. (登録日: 2021-01-07, 公開日: 2021-04-14, 最終更新日: 2024-10-23)

主引用文献

Deng, W.,Chen, X.,Jiang, K.,Song, X.,Huang, M.,Tu, Z.C.,Zhang, Z.,Lin, X.,Ortega, R.,Patterson, A.V.,Smaill, J.B.,Ding, K.,Chen, S.,Chen, Y.,Lu, X.
Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors.
Acs Med.Chem.Lett., 12:647-652, 2021

PubMed Abstract: Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds , , and selectively suppressed FGFR4 enzymatic activity with IC values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. and might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

PubMed: 33859803
DOI: 10.1021/acsmedchemlett.1c00052

実験手法

X-RAY DIFFRACTION (2.01 Å)