期刊
PHARMACEUTICALS
卷 15, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/ph15111322
关键词
kinase inhibitor; covalent kinase inhibitor; privileged warhead; nucleophile; rational drug discovery
资金
- University of Virginia
This article reviews the recent developments in covalent kinase inhibitors (CKIs) and discusses their characteristics, including the features of nucleophilic amino acids and preferences of electrophilic warheads. It also explores trends in CKI development across the whole proteome.
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.
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