Design, synthesis and biological evaluation of pteridine-7(8H)-one derivatives as potent and selective CDK4/6 inhibitors

Abstract

Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in the treatment of cancer. In this article, we described the design and synthesis of a series of pteridine-7(8H)-one derivatives as dual CDK4/6 inhibitors. Among them, the most promising compound L2 exhibited significant inhibitory activity against CDK4 and CDK6 with IC₅₀ values of 16.7 nM and 30.5 nM respectively and showed excellent selectivity to CDK1/2/7/9. Moreover, compound L2 displayed potent antiproliferative activities at low digital micromolar range via inducing apoptosis in breast and colon cancer cells. In all, we developed a new series of pteridine-7(8H)-one derivatives which exhibited promising antitumor activities as selective CDK4/6 inhibitors.

Keywords: CDK4/6 inhibitors; Scaffold hopping; Structure-activity relationships.