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Lysine‐Targeting Covalent Inhibitors
Author(s) -
Pettinger Jonathan,
Jones Keith,
Cheeseman Matthew D.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201707630
Subject(s) - lysine , drug discovery , cysteine , chemistry , combinatorial chemistry , small molecule , covalent bond , electrophile , biochemistry , computational biology , amino acid , enzyme , biology , organic chemistry , catalysis
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.