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
Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors

文献类型：期刊论文

作者Gao, Dingding1,3; Jin, Nan2; Fu, Yixian2,4; Zhu, Yueyue1; Wang, Yujie1; Wang, Ting2; Chen, Yuehong2; Zhang, Mingming1; Xiao, Qiang1; Huang, Min2,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-04-15
卷号216页码:20
ISSN号0223-5234
关键词STAT3 signaling pathway Benzothiazole Rational design Antitumor activity Molecular docking
DOI10.1016/j.ejmech.2021.113333
通讯作者Li, Yingxia(liyx417@fudan.edu.cn)
英文摘要The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067 mu M as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment. (C) 2021 Elsevier Masson SAS. All rights reserved.
资助项目Significant New Drugs Development[2018ZX09711002-003-009] ; National Natural Science Foundation of China[81973178] ; National Natural Science Foundation of China[U1906212]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000637742700032
源URL[http://119.78.100.183/handle/2S10ELR8/296636]  
专题新药研究国家重点实验室
通讯作者Li, Yingxia
作者单位1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med IRI, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Dingding,Jin, Nan,Fu, Yixian,et al. Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,216:20.
APA Gao, Dingding.,Jin, Nan.,Fu, Yixian.,Zhu, Yueyue.,Wang, Yujie.,...&Li, Yingxia.(2021).Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,216,20.
MLA Gao, Dingding,et al."Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 216(2021):20.

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。