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Therapeutics, Targets, and Chemical Biology

Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer Meagher, Jeanne Stuckey, Daniel F. Hayes, Shunqiang Li, Matthew J. Ellis and Shaomeng Wang
Longchuan Bai
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Bing Zhou
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Chao-Yie Yang
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Jiao Ji
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Donna McEachern
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Sally Przybranowski
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Hui Jiang
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
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Jiantao Hu
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Fuming Xu
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Yujun Zhao
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Liu Liu
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Ester Fernandez-Salas
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Jing Xu
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Yali Dou
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Bo Wen
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan.
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Duxin Sun
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan.
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Jennifer Meagher
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
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Jeanne Stuckey
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
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Daniel F. Hayes
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Shunqiang Li
Division of Oncology, Department of Internal Medicine, Section of Breast Oncology, Washington University in St. Louis, St. Louis, Missouri.
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Matthew J. Ellis
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
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Shaomeng Wang
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.Department of Pharmacology, University of Michigan, Ann Arbor, Michigan.Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan.
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  • For correspondence: shaomeng@umich.edu
DOI: 10.1158/0008-5472.CAN-16-2622
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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); 1–12. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received September 28, 2016.
  • Revision received October 31, 2016.
  • Accepted January 25, 2017.
  • ©2017 American Association for Cancer Research.
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Published OnlineFirst April 20, 2017
doi: 10.1158/0008-5472.CAN-16-2622

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Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer Meagher, Jeanne Stuckey, Daniel F. Hayes, Shunqiang Li, Matthew J. Ellis and Shaomeng Wang
Cancer Res April 20 2017 DOI: 10.1158/0008-5472.CAN-16-2622

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Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer Meagher, Jeanne Stuckey, Daniel F. Hayes, Shunqiang Li, Matthew J. Ellis and Shaomeng Wang
Cancer Res April 20 2017 DOI: 10.1158/0008-5472.CAN-16-2622
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