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.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs.
Thursday, October 7, 2021
Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition
Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...
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Katharine Gilbert, Aini Vuorinen, Arron Aatkar Peter Pogány, Jonathan Pettinger, Joanna M. Kirkpatrick, Katrin Rittinger∥, David House, Glen...
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Yejin Jung, Naotaka Noda, Junichiro Takaya, Masahiro Abo, Kohei Toh, Ken Tajiri, Changyi Cui, Lu Zhou, Shin-ichi Sato, and Motonari Uesugi A...
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Madeline E Kavanagh, Benjamin D Horning, Roli Khattri, Nilotpal Roy, Justine P Lu, Landon R Whitby, Jaclyn C Brannon, Albert Parker, Joel M ...