Discovery of CDK5 Inhibitors through Structure-Guided Approach

Specific abrogation of cyclin dependent kinase 5 (CDK5) activity has been validated as a viable approach for the development of anticancer agents. However, no selective CDK5 inhibitor has been reported to date. Herein, a structure-based in silico screening was employed to identify novel scaffolds from a library of compounds to identify potential CDK5 inhibitors which would be rele-vant for drug discovery. Hits, representatives of three chemical classes, were identified as inhibitors of CDK5. Structural modifi-cation of hit-1 resulted in 29 and 30. Compound 29 is a dual inhibitor of CDK5 and CDK2, whereas 30 preferentially inhibits CDK5. Both leads exhibited anticancer activity against acute myeloid leukemia (AML) cells via a mechanism consistent with tar-geting cellular CDK5. This study provides an effective strategy for development of CDK5 inhibitors as potential anti-leukemic agents.