Development of Dihydroquinoxalinone-Based Dual CDK6/BET Inhibitors for Triple-Negative Breast Cancer Therapy

The clinical application of CDK4/6 inhibitors is constrained by their narrow indications. To improve therapeutic efficacy against breast cancer, combination therapies using CDK4/6 inhibitors with BET inhibitors are being explored in clinical trials. Our study demonstrates that the CDK4/6 inhibitor Abemaciclib and the BRD4 inhibitor BQ0 exert a synergistic effect in inhibiting the proliferation of triple-negative breast cancer (TNBC) cells in vitro. Based on these findings, we designed and synthesized a series of dual-target inhibitors that simultaneously target CDK6 and BRD4. Among the newly synthesized compounds, <b>7f</b> and <b>7f15</b> exhibited potent inhibitory activity against both CDK6 and BRD4, along with remarkable antiproliferative activity on TNBC cells. In vivo studies using the MDA-MB-231 xenograft mouse model revealed that <b>7f15</b> exhibits robust antitumor activity without significant adverse effects. The kinases selectivity experimental suggested that <b>7f15</b> is a pan-BET inhibitor. In summary, <b>7f15</b>, hereby designated as <b>KWZL-7f15</b>, is a novel dual CDK6/BET inhibitor with promising therapeutic potential for the treatment of triple-negative breast cancer.