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

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.