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Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors. 2021

Wuqing Deng, and Xiaojuan Chen, and Kaili Jiang, and Xiaojuan Song, and Minhao Huang, and Zheng-Chao Tu, and Zhang Zhang, and Xiaojing Lin, and Raquel Ortega, and Adam V Patterson, and Jeff B Smaill, and Ke Ding, and Suming Chen, and Yongheng Chen, and Xiaoyun Lu
School of Pharmacy, Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China.

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 6a, 6h, and 6i selectively suppressed FGFR4 enzymatic activity with IC50 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 6h bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound 6i with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. 6h and 6i might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

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