Lysine-Targeting Covalent Inhibitors.

Autor: Pettinger J; Cancer Research, UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP, UK., Jones K; Cancer Research, UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP, UK., Cheeseman MD; Cancer Research, UK, Cancer Therapeutics Unit, The Institute of Cancer Research, London, SW7 3RP, UK.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2017 Nov 27; Vol. 56 (48), pp. 15200-15209. Date of Electronic Publication: 2017 Oct 27.
DOI: 10.1002/anie.201707630
Abstrakt: 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.
(© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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