Discovery of Dual CDK6/BRD4 Inhibitor Inducing Apoptosis and Increasing the Sensitivity of Ferroptosis in Triple-Negative Breast Cancer

Bromodomain-containing protein 4 (BRD4) is the most promising target for the treatment of triple-negative breast cancer (TNBC). However, its inherent resistant and acquired drug resistance limits its potential clinical application. Recently it has been shown that cyclin-dependent kinases 4/6 (CDK4/6) inhibitors can reincrease the sensitivity of TNBC cells to BRD4 inhibitors by combination therapy, so we designed a series of dual target CDK6/BRD4 inhibitors. Among the newly synthesized compounds, <b>BC13</b> exhibited potent inhibitory activity against CDK6 and BRD4. It also displayed potent antiproliferative activity against TNBC cells. In vivo experiments showed that <b>BC13</b> has potent antitumor activity in the MDA-MB-231 xenograft mouse model, without observable side effects. <b>BC13</b> demonstrates profound synergistic antitumor effects with ferroptosis inducer in TNBC cells. Therefore, <b>BC13</b> is a novel dual inhibitor of CDK6/BRD4 for the treatment of TNBC either as a single agent or in combination with RSL3.