Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity

Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography. (c) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

Haspin is a potential target for the development of anticancer drugs, but current inhibitors show poor selectivity for human kinome. A new inhibitor with excellent activity and selectivity for Haspin has been identified, and its binding mode with Haspin has been determined through crystallography.