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

Zhen Zhang; Yongjin Wang; Xiaojuan Chen; Xiaojuan Song; Zhengchao Tu; Yongheng Chen; Zhimin Zhang; Ke Ding

doi:10.1016/j.bmc.2021.116457

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. Epub 2021 Oct 5.

Authors

Zhen Zhang¹, Yongjin Wang¹, Xiaojuan Chen², Xiaojuan Song³, Zhengchao Tu⁴, Yongheng Chen², Zhimin Zhang¹, Ke Ding⁵

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: dingke@jnu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Hydrocarbons, Fluorinated / chemical synthesis
Hydrocarbons, Fluorinated / chemistry
Hydrocarbons, Fluorinated / pharmacology*
Janus Kinase 3 / antagonists & inhibitors*
Janus Kinase 3 / metabolism
Ketones / chemical synthesis
Ketones / chemistry
Ketones / pharmacology*
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Hydrocarbons, Fluorinated
Ketones
Protein Kinase Inhibitors
JAK3 protein, human
Janus Kinase 3