Systematic exploration of privileged warheads for covalent kinase drug discovery

16 August 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Drug Design and Discovery
Kinase Drugs
Covalent Inhibitors
Privileged Warheads
Reversible Covalent Kinase Inhibitors
Drug Screening


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