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. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Thursday, October 7, 2021
Discovery and Optimization of a Covalent AKR1C3 Inhibitor
R. Justin Grams, Wesley J. Wolfe, Robert J. Seal, James Veccia, and Ku-Lung Hsu Journal of Medicinal Chemistry 2025 DOI: 10.1021/acs.jmedch...
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DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
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Özge Ünsal, Z. Selin Bacaksiz, Vladislav Khamraev, Vittorio Montanari, Martin Beinborn, and Krishna Kumar ACS Chemical Biology 2024 DOI: ...
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Klett, T., Schwer, M., Ernst, L. N., Engelhardt, M. U., Jaag, S. J., Masberg, B., … Boeckler, F. M. Drug Design, Development and Therapy, 20...