Scaffold Hopping Approach to a New Series of Pyridine Derivatives as Potent Inhibitors of CDK2

Abstract

A scaffold hopping approach was exploited to guide the discovery of a series of pyridine derivatives as novel cyclin-dependent kinase (CDK2) inhibitors. These new compounds were designed, synthesized, and evaluated as CDK2 inhibitors. Most of the compounds showed potent inhibition against CDK2, and preliminary structure-activity relationship trends were revealed. A docking study on the most potent compound 6g implied the structural basis for potent CDK2 inhibition. All of the synthesized compounds were also evaluated for their cytotoxicity against the H522 and U87 cancer cell lines. The most potent and drug-like compound 6g was further tested against a normal cell line (L02), demonstrating that this compound is selectively toxic toward cancer cell lines. The results provide the foundation for further improving the potency of this series of compounds.