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|Ref Type||Journal Article|
|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.|
|Date||2017 May 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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 + 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|
|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|