2. Academic Validation
  3. Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design

Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design

  • Bioorg Med Chem. 2021 Nov 15;50:116457. doi: 10.1016/j.bmc.2021.116457.
Zhen Zhang 1,  Yongjin Wang 1,  Xiaojuan Chen 2,  Xiaojuan Song 3,  Zhengchao Tu 4,  Yongheng Chen 2,  Zhimin Zhang 1,  Ke Ding 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 3 Drug Discovery Pipeline & Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; Drug Discovery Pipeline & Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; The First Affiliated Hospital, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: [email protected].
PMID: 34670167 DOI: 10.1016/j.bmc.2021.116457
Abstract

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 Inhibitor, suggesting its potential application in designing other kinase inhibitors.

Keywords

Aromatic trifluoromethyl ketone; Covalently; Reversible; Warhead.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146541
    FGFR4 Inhibitor