Thursday, October 7, 2021

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,

Bioorganic & Medicinal Chemistry,2021, 116457,

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.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...