Biological and Medicinal Chemistry

Systematic exploration of privileged warheads for covalent kinase drug discovery

Authors

  • Zheng Zhao School of Data Science and Department of Biomedical Engineering, University of Virginia ,
  • Philip E. Bourne School of Data Science and Department of Biomedical Engineering, University of Virginia

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.

Content

Thumbnail image of Privileged_warhead_forchemrxiv.pdf