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, 7f and 7f15 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 7f15 exhibits robust antitumor activity without significant adverse effects. The kinases selectivity experimental suggested that 7f15 is a pan-BET inhibitor. In summary, 7f15, hereby designated as KWZL-7f15, is a novel dual CDK6/BET inhibitor with promising therapeutic potential for the treatment of triple-negative breast cancer.