Journal
CANCER RESEARCH
Volume 77, Issue 9, Pages 2476-2487Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-2622
Keywords
-
Categories
Funding
- Breast Cancer Research Foundation
- University of Michigan Comprehensive Cancer Center Strategic Fund for Breast Cancer
- University of Michigan Comprehensive Cancer Center Core grant from National Cancer Institute, NIH [P30CA046592]
- Susan G. Komen for the Cure Promise Grant [PG12220321]
Ask authors/readers for more resources
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 protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET proteins at low nanomolar concentrations within 1 hour 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 with BETi-211 treatment that upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector for 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 that targeting BET proteins for degradation represents an effective therapeutic strategy for TNBC treatment. Cancer Res; 77(9); 2476-87. (C) 2017 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available