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

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.

Automated summary

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for designing covalently reversible kinase inhibitors targeting non-catalytic cysteine residue. It successfully led to the design and synthesis of potent and selective inhibitors for FGFR4 kinase. Furthermore, this functional group was also applied to the discovery of a new JAK3 inhibitor, indicating its potential in designing other kinase inhibitors.