2. Academic Validation
  3. Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors

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

  • ACS Med Chem Lett. 2021 Mar 22;12(4):647-652. doi: 10.1021/acsmedchemlett.1c00052.
Wuqing Deng 1,  Xiaojuan Chen 2,  Kaili Jiang 1,  Xiaojuan Song 3,  Minhao Huang 3,  Zheng-Chao Tu 3,  Zhang Zhang 1,  Xiaojing Lin 4,  Raquel Ortega 4,  Adam V Patterson 5 4,  Jeff B Smaill 5 4,  Ke Ding 1,  Suming Chen 6,  Yongheng Chen 2,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 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.
  • 3 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 4 Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 5 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 6 Yancheng Dafeng People's Hospital, #139 Xingfu East Road, Dafeng District,Yancheng 224100, China.
PMID: 33859803 DOI: 10.1021/acsmedchemlett.1c00052
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 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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