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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. | ||||||||||||
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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 |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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BETd-246 | BET-d246 | BRD2 Inhibitor 1 BRD3 Inhibitor 2 BRD4 Inhibitor 10 | 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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