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 - 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 - https://www.scopus.com/pages/publications/85019050301
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 -