Discovery of dual CDK4/6 and BRD4 inhibitor as apoptosis and autophagy inducers against NSCLC in vitro and in vivo.

Target of cyclin dependent kinase (CDK) by inhibitors has demonstrated promising potential as a therapeutic agent for cancer. However, the efficacy of monotherapy on tumors is limited and there is an urgent need for combination therapy with other inhibitors. It has been reported that restoring bromodomain-containing protein 4 (BRD4) resensitivity to tumor cells by inhibiting CDK4/6 is a potential therapeutic strategy. In this study, we present the design and optimization of dual CDK4/6 and BRD4 inhibitors, among which B15 exhibited potent and selective inhibition of both targets in vitro, and significant antiproliferative effects in non-small cell lung cancer (NSCLC) cells. Importantly, it also showed good pharmacokinetic properties in rats, meanwhile, B15 effectively inhibited tumor growth in vivo (TGI = 85.3 %) without causing significant toxicity. Overall, our results introduce a promising strategy of dual CDK4/6 and BRD4 inhibitors for the treatment of NSCLC.