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.