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

Abstract

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, BC13 exhibited potent inhibitory activity against CDK6 and BRD4. It also displayed potent antiproliferative activity against TNBC cells. In vivo experiments showed that BC13 has potent antitumor activity in the MDA-MB-231 xenograft mouse model, without observable side effects. BC13 demonstrates profound synergistic antitumor effects with ferroptosis inducer in TNBC cells. Therefore, BC13 is a novel dual inhibitor of CDK6/BRD4 for the treatment of TNBC either as a single agent or in combination with RSL3.