TY - JOUR
T1 - Targeted degradation of BET proteins in triple-negative breast cancer
AU - Bai, Longchuan
AU - Zhou, Bing
AU - Yang, Chao Yie
AU - Ji, Jiao
AU - McEachern, Donna
AU - Przybranowski, Sally
AU - Jiang, Hui
AU - Hu, Jiantao
AU - Xu, Fuming
AU - Zhao, Yujun
AU - Liu, Liu
AU - Fernandez-Salas, Ester
AU - Xu, Jing
AU - Dou, Yali
AU - Wen, Bo
AU - Sun, Duxin
AU - Meagher, Jennifer
AU - Stuckey, Jeanne
AU - Hayes, Daniel F.
AU - Li, Shunqiang
AU - Ellis, Matthew J.
AU - Wang, Shaomeng
N1 - Funding Information:
The Breast Cancer Research Foundation (to S. Wang), the University of Michigan Comprehensive Cancer Center Strategic Fund for Breast Cancer (to S. Wang), the University of Michigan Comprehensive Cancer Center Core grant (to S. Wang as a program leader) from the National Cancer Institute, NIH (P30CA046592), and the Susan G. Komen for the Cure Promise Grant (PG12220321 to S. Wang and M. J. Ellis).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019050301&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-2622
DO - 10.1158/0008-5472.CAN-16-2622
M3 - Article
C2 - 28209615
AN - SCOPUS:85019050301
SN - 0008-5472
VL - 77
SP - 2476
EP - 2487
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -