Deng Wuqing, Chen Xiaojuan, Jiang Kaili, Song Xiaojuan, Huang Minhao, Tu Zheng-Chao, Zhang Zhang, Lin Xiaojing, Ortega Raquel, Patterson Adam V, Smaill Jeff B, Ding Ke, Chen Suming, Chen Yongheng, Lu Xiaoyun
School of Pharmacy, Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China.
Department of Oncology, NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
ACS Med Chem Lett. 2021 Mar 22;12(4):647-652. doi: 10.1021/acsmedchemlett.1c00052. eCollection 2021 Apr 8.
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.
共价激酶抑制剂正迅速成为一类具有临床益处的治疗药物。在此，我们报告了一系列基于2-氨基嘧啶的选择性成纤维细胞生长因子受体4（FGFR4）抑制剂，探索了不同类型的靶向半胱氨酸弹头。构效关系研究表明，化学调谐的弹头α-氟丙烯酰胺、乙烯基磺酰胺和乙醛胺适合作为设计选择性FGFR4抑制剂的共价弹头。化合物、和分别以53±18、45±11和16±4 nM的IC值选择性抑制FGFR4酶活性，同时保留FGFR1/2/3。X射线晶体结构和基质辅助激光解吸电离飞行时间研究表明，带有α-氟丙烯酰胺的化合物以不可逆结合模式与FGFR4结合，而带有乙醛胺的化合物以可逆共价模式与FGFR4结合。和可能为合理设计新型选择性FGFR4抑制剂提供一些基本结构信息。
