| Literature DB >> 28209615 |
Longchuan Bai1,2, Bing Zhou1,2, Chao-Yie Yang1,2, Jiao Ji1,2, Donna McEachern1,2, Sally Przybranowski1,2, Hui Jiang1,3, Jiantao Hu1,2, Fuming Xu1,2, Yujun Zhao1,2, Liu Liu1,2, Ester Fernandez-Salas1,2,4, Jing Xu1,4, Yali Dou1,4, Bo Wen1,5, Duxin Sun1,5, Jennifer Meagher6, Jeanne Stuckey6, Daniel F Hayes1,2, Shunqiang Li7, Matthew J Ellis8, Shaomeng Wang9,2,10,11.
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. ©2017 American Association for Cancer Research.Entities:
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Year: 2017 PMID： 28209615 PMCID： PMC5413378 DOI： 10.1158/0008-5472.CAN-16-2622
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 12.701