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Ref Type Journal Article
PMID (28209615)
Authors Bai L, Zhou B, Yang CY, 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 DF, Li S, Ellis MJ, Wang S
Title Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer.
Journal Cancer research
Vol 77
Issue 9
Date 2017 May 01
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BETd-246 BETd-246 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
BETd-246 BET-d246 BRD2 Inhibitor 1 BRD3 Inhibitor 2 BRD4 Inhibitor 7 BETd-246 is a small molecule that induces degradation of Brd2, Brd3, and Brd4 proteins, leading to apoptosis of tumor cells (PMID: 28209615, PMID: 30797188).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown triple-receptor negative breast cancer not applicable BETd-246 + BM-1197 Preclinical - Cell culture Actionable In a preclinical study, the Bet inhibitor BETd-246 and the Bcl-xl inhibitor BM-1197 synergistically induced apoptosis in triple-receptor negative breast cancer cell lines in culture (PMID: 28209615). 28209615
Unknown unknown triple-receptor negative breast cancer not applicable BETd-246 + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, the Bet inhibitor BETd-246 and the Bcl-xl inhibitor ABT-263 synergistically induced apoptosis in triple-receptor negative breast cancer cell lines in culture (PMID: 28209615). 28209615
Unknown unknown triple-receptor negative breast cancer not applicable A-1155463 + BETd-246 Preclinical - Cell culture Actionable In a preclinical study, the Bet inhibitor BETd-246 and the Bcl-xl inhibitor A-1155463 synergistically induced apoptosis in triple-receptor negative breast cancer cell lines in culture (PMID: 28209615). 28209615