Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Open accessPublished version of a preprint
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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Many PROTACs are not completely selective and can degrade proteins other than their desired targets.
“In addition, many PROTACs are not completely selective and can degrade proteins other than their desired targets [7, 90, 204, 205].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [90]
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References 50 · Cited by 199
- Authors
- Bai, L., Zhou, B., Yang, C.-Y., Ji, J., McEachern, D., Przybranowski, S., Jiang, H., Hu, J., Xu, F., Zhao, Y., Liu, L., Fernandez-Salas, E., Xu, J., Dou, Y., Wen, B., Sun, D., Meagher, J., Stuckey, J., Hayes, D. F., Li, S., Ellis, M. J., & Wang, S.
- Affiliations
- University of Michigan (US)
- 1University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
- Washington University in St. Louis (US)
- Baylor College of Medicine (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Cancer Research
- Published
- 2017-04-30
- Volume
- 77
- Issue
- 9
- Pages
- 2476-2487
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5413378
- OpenAlex
- W2589078946
- Cited by
- 199
- References
- 50
- Citations by year
- 2026: 3 · 2025: 18 · 2024: 22 · 2023: 18 · 2022: 23 · 2021: 32 · 2020: 27 · 2019: 34 · 2018: 10 · 2017: 12
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan
- National Cancer Institute (P30CA046592)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- triple-negative breast cancer, BET proteins, Mcl-1, Bcl-xL inhibitors, apoptosis, gene expression profiling, xenograft models, targeted therapy
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Nerve Tissue Proteins, Receptors, Cell Surface, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, High-Throughput Nucleotide Sequencing, Proteolysis, Myeloid Cell Leukemia Sequence 1 Protein, Triple Negative Breast Neoplasms
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