Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211. RNA-seq analysis revealed predominant downregulation of a large number of genes involved in proliferation and apoptosis in cells treated with BETd-246, as compared to BETi-211 treatment which upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector of these BET degraders, which synergized with small molecule inhibitors of BCL-xL in triggering apoptosis. In multiple murine xenograft models of human breast cancer, BETd-246 and a further optimized analogue BETd-260 effectively depleted BET proteins in tumors and exhibited strong antitumor activities at well-tolerated dosing schedules. Overall, our findings show how specific targeting of BET proteins for degradation yields an effective therapeutic strategy for TNBC treatment.
- Received September 28, 2016.
- Revision received January 4, 2017.
- Accepted January 25, 2017.
- Copyright ©2017, American Association for Cancer Research.