Open AccessInvestigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors
Author(s) -
Wuqing Deng,
Xiaojuan Chen,
Kaili Jiang,
Xiaojuan Song,
Ming Huang,
Zhengchao Tu,
Zhang Zhang,
Xiaojing Lin,
Raquel Ortega,
Adam V. Patterson,
Jeff B. Smaill,
Ke Ding,
Suming Chen,
Yongheng Chen,
Xiaoyun Lu
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00052
Subject(s) - chemistry , acrylamide , covalent bond , fibroblast growth factor receptor , fibroblast growth factor receptor 4 , amine gas treating , cysteine , biochemistry , combinatorial chemistry , enzyme , organic chemistry , polymer , receptor , fibroblast growth factor , copolymer
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 IC 50 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.