中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1

文献类型：期刊论文

作者Wu, Qian1,2; Chen, Dan-Qi3; Sun, Lin1,2; Huan, Xia-Juan1; Bao, Xu-Bin1; Tian, Chang-Qing1,2; Hu, Jianping3; Lv, Kai-Kai2,3; Wang, Ying-Qing1,2; Xiong, Bing2,3
刊名BIOCHEMICAL PHARMACOLOGY
出版日期2021-03-01
卷号185页码:14
关键词N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity
ISSN号0006-2952
DOI10.1016/j.bcp.2021.114435
通讯作者Wang, Ying-Qing(yqwang@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn)
英文摘要Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.
资助项目National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-018] ; Science and Technology Commission of Shanghai Municipality[19ZR1467900] ; Science and Technology Commission of Shanghai Municipality[20ZR1468100] ; Nova Development Program of the Shanghai Institute of Materia Medica ; Chinese Academy of Sciences ; State Key Laboratory of Drug Research
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000634804200003
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/295302]  
专题新药研究国家重点实验室
通讯作者Wang, Ying-Qing; Xiong, Bing; Miao, Ze-Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 501 Haike Rd, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Qian,Chen, Dan-Qi,Sun, Lin,et al. Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1[J]. BIOCHEMICAL PHARMACOLOGY,2021,185:14.
APA Wu, Qian.,Chen, Dan-Qi.,Sun, Lin.,Huan, Xia-Juan.,Bao, Xu-Bin.,...&Miao, Ze-Hong.(2021).Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1.BIOCHEMICAL PHARMACOLOGY,185,14.
MLA Wu, Qian,et al."Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1".BIOCHEMICAL PHARMACOLOGY 185(2021):14.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。