title: Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer.
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 theMCL1gene 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.
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Longchuan
authors.initials: L
authors.lastname: Bai
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jiao
authors.initials: J
authors.lastname: Ji
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sally
authors.initials: S
authors.lastname: Przybranowski
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Hu
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Fuming
authors.initials: F
authors.lastname: Xu
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Ester
authors.initials: E
authors.lastname: Fernandez-Salas
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meagher
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Stuckey
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Division of Oncology, Department of Internal Medicine, Section of Breast Oncology, Washington University in St. Louis, St. Louis, Missouri.
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. shaomeng@umich.edu.|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.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C462501:DNER protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface