Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 50, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116457
Keywords
Aromatic trifluoromethyl ketone; Covalently; Reversible; Warhead
Funding
- National Natural Science Foundation of China [22037003, 81820108029, 81874284]
- Guangdong Province [2018B030337001, 2018A030313685, 2020A0505140007]
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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.
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.
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