Jonathan Pettinger, Keith Jones, Matthew David Cheeseman
Angewandte Chemie International Edition, 2017
DOI: 10.1002/anie.201707630
Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small molecule/protein crystal structures to design tight-binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ε-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples and present recent developments that demonstrate its potential for future drug discovery.
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
Introduction of Reactive Thiol Handles into Tyrosine-Tagged Proteins through Enzymatic Oxidative Coupling
Paul Huang, Wendy Cao, Jennifer L. Fetzer, Nicholas S. Dolan, Matthew B. Francis J. Am. Chem. Soc. 2025 https://doi.org/10.1021/jacs.5c06195...
-
Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitorDandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Jo...
-
DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
-
George S. Biggs, Emma E. Cawood, Aini Vuorinen, William J. McCarthy, Harry Wilders, Ioannis G. Riziotis, Antonie J. van der Zouwen, Jonathan...