Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

  • Cancer Res. 2017 May 1;77(9):2476-2487. doi: 10.1158/0008-5472.CAN-16-2622.
Longchuan Bai  1  2 ,  Bing Zhou  1  2 ,  Chao-Yie Yang  1  2 ,  Jiao Ji  1  2 ,  Donna McEachern  1  2 ,  Sally Przybranowski  1  2 ,  Hui Jiang  1  3 ,  Jiantao Hu  1  2 ,  Fuming Xu  1  2 ,  Yujun Zhao  1  2 ,  Liu Liu  1  2 ,  Ester Fernandez-Salas  1  2  4 ,  Jing Xu  1  4 ,  Yali Dou  1  4 ,  Bo Wen  1  5 ,  Duxin Sun  1  5 ,  Jennifer Meagher  6 ,  Jeanne Stuckey  6 ,  Daniel F Hayes  1  2 ,  Shunqiang Li  7 ,  Matthew J Ellis  8 ,  Shaomeng Wang  9  2  10  11
Affiliations
  • 1. University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
  • 2. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • 3. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
  • 4. Department of Pathology, University of Michigan, Ann Arbor, Michigan.
  • 5. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan.
  • 6. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
  • 7. Division of Oncology, Department of Internal Medicine, Section of Breast Oncology, Washington University in St. Louis, St. Louis, Missouri.
  • 8. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
  • 9. University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. [email protected].
  • 10. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan.
  • 11. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan.
PMID: 28209615 DOI: 10.1158/0008-5472.CAN-16-2622
Abstract

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. ©2017 AACR.

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