Lysine-Targeting Covalent Inhibitors.
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ICR Authors
Authors
Pettinger, J
Jones, K
Cheeseman, MD
Jones, K
Cheeseman, MD
Document Type
Journal Article
Date
2017-11-27
Date Accepted
2017-08-29
Abstract
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 tightly 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 the potential of lysine targeting for future drug discovery.
Citation
Angewandte Chemie (International ed. in English), 2017, 56 (48), pp. 15200 - 15209
Source Title
Publisher
WILEY-V C H VERLAG GMBH
ISSN
1433-7851
eISSN
1521-3773
Collections
Research Team
Medicinal Chemistry 3