文献类型：期刊文献

英文题名：Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer

作者：He, Shipeng[1,2,3];Dong, Guoqiang[1];Li, Yu[1];Wu, Shanchao[1];Wang, Wei[2,4,5];Sheng, Chunquan[1,6]

机构：[1]Second Mil Med Univ, Sch Pharm, 325 Guohe Rd, Shanghai 200433, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China;[3]Shanghai Univ, Inst Translat Med, 99 Shangda Rd, Shanghai 200444, Peoples R China;[4]Univ Arizona, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA;[5]Univ Arizona, Inst BIO5, Tucson, AZ 85721 USA;[6]Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China

年份：2020

卷号：59

期号：8

起止页码：3028

外文期刊名：ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

收录：;EI(收录号：20200608128565);WOS:【SCI-EXPANDED(收录号:WOS:000519891700047)】；

基金：This work was supported by National Natural Science Foundation of China (21738002, 81725020, and 81872742), the National Key R&D Program of China (2017YFA0506000), and the Innovation Program of Shanghai Municipal Education Commission (Grant 2019-01-07-00-07-E00073).

语种：英文

外文关键词：anticancer; antitumor agents; drug discovery; heterocyles; inhibitors

摘要：As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small-molecule inhibitors that simultaneously target bromodomain and extra-terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor (13 a) is identified to possess excellent and balanced activities against BRD4 BD1 (IC50=11 nm) and HDAC1 (IC50=21 nm). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)-JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.