Synthesis and Evaluation of a 3,4-dihydro-2H-benzoxazine Derivative as a Potent CDK9 Inhibitor for Anticancer Therapy

Abstract

Cyclin-dependent kinase (CDK) 9 is a protein kinase that plays a major regulatory role in the process of transcription, thereby representing an attractive target in cancer therapy. A series of novel, highly potent, selective derivatives (coined compounds 8-15) were designed, synthesized, and evaluated for their inhibitory effect on CDK functions using cancer cell lines. Here, we showed that our compound 8 exhibited a potent CDK9 inhibitory activity in ICR mice, with an IC50 value of 2.3 nM as well as favorable pharmacokinetic properties. Using an MV4-11 xenograft mouse model, compound 8 showed antitumor efficacy at a dose of 10 mg/kg; compound 8 treatment was well tolerated, with no adverse effects on body weight or animal health. Our in vitro and in vivo findings strongly suggest that compound 8 holds great promise for the development of highly potent CDK9 inhibitors in anticancer approaches.