Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery.

Content Provider	Europe PMC
Author	Zhao, Zheng Bourne, Philip E.
Editor	Gehringer, Matthias Borsari, Chiara Serafim, Ricardo Augusto Massarico Colotta, Vittoria
Copyright Year	2022
Abstract	Kinase-targeted drug discovery for cancer therapy has advanced significantly in the last three decades. Currently, diverse kinase inhibitors or degraders have been reported, such as allosteric inhibitors, covalent inhibitors, macrocyclic inhibitors, and PROTAC degraders. Out of these, covalent kinase inhibitors (CKIs) have been attracting attention due to their enhanced selectivity and exceptionally strong affinity. Eight covalent kinase drugs have been FDA-approved thus far. Here, we review current developments in CKIs. We explore the characteristics of the CKIs: the features of nucleophilic amino acids and the preferences of electrophilic warheads. We provide systematic insights into privileged warheads for repurposing to other kinase targets. Finally, we discuss trends in CKI development across the whole proteome.
Volume Number	15
PubMed Central reference number	PMC9695834
Issue Number	11
PubMed reference number	36355497
Journal	Pharmaceuticals (Basel)
e-ISSN	14248247
DOI	10.3390/ph15111322
Language	English
Publisher	MDPI
Publisher Date	2022-10-26
Access Restriction	Open
Rights License	Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). © 2022 by the authors.
Subject Keyword	kinase inhibitor covalent kinase inhibitor privileged warhead nucleophile rational drug discovery
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Pharmaceutical Science Molecular Medicine