2. Academic Validation
  3. Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

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

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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