Inhibitors of Cyclin-Dependent Kinase 1/2 for Anticancer Treatment

Abstract

Background: The cell cycle is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins, along with their endogenous inhibitors (CDKIs). CDKs act as central regulators in this process. Different CDKs play relevant roles in different phases. Among all CDKs, CDK1 is indispensible, which can drive all events that are required in the cell cycle in the absence of interphase CDKs (CDK2, CDK3, CDK4 and CDK6). So, CDK1 is an attractive target for anticancer drug development. Methods: CDK1 and CDK2 have 89.19% similar residues and 74.32% identical residues, their structures especially the ATP-binding sites are of great similarity. So, it is difficult to inhibit CDK1 and CDK2 individually. In this review, recent advances about CDK1/2 inhibitors were summarized. The chemical structures of different classes of CDK1/2 inhibitors and their structure activity are presented. Results: 19 kinds of CDK1/2 or CDK1 inhibitors with different scaffolds, including CDK2 allosteric inhibitors, were summarized. Some inhibitors are nature derived, for example, phenanthrene derivatives, nortopsentin derivatives, variolin B derivatives and meridians. Conclusion: Nature products, especially marine ones are potential resources for CDK1 inhibitors development. The findings of CDK2 allosteric inhibitors open an avenue to the discovery of novel selective CDK1 or other CDKs allosteric inhibitors.