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
Discovery of novel Thieno[2,3-d]imidazole derivatives as agonists of human STING for antitumor immunotherapy using systemic administration

文献类型：期刊论文

作者Niu, Jing6,7; Bai, Hudagula3,5; Li, Zizhou6; Gao, Yuzhe6; Zhang, Yan5; Wang, Xiyuan5; Yang, Yaxi4,6; Xu, Yungen7; Geng, Meiyu3,5; Xie, Zuoquan3,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-08-05
卷号238页码:16
ISSN号0223-5234
关键词STING cGAS Non-cyclic dinucleotides (non-CDNs) Systemic administration Antitumor immunotherapy
DOI10.1016/j.wjmech.2022.114482
通讯作者Xu, Yungen(xyg64@126.com) ; Xie, Zuoquan(zqxie@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC50 value of 1.2 nM. Compound 45 was found to bind to multiple human STING isoforms and accordingly activated the downstream TBK1/IRF3 and NF-kappa B signaling pathways in the reporter cells bearing with different STING isoforms. The activation on STING signaling pathway was abolished in the STING knock-out cells, indicating that it is a specific STING agonist. Compound 45 significantly inhibited the tumor growth in allograft 4T1 and CT26 tumor models by systemic administration, and more significantly, 45 was able to induce tumor regression in CT26 tumor model without inducing weight loss, suggesting that compound 45 is a highly promising candidate worthy for further development.
WOS关键词CYCLIC GMP-AMP ; POTENT ; 2ND-MESSENGER ; RECOGNITION ; PATHWAY ; DESIGN ; SENSOR
资助项目National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[81773568] ; National Natural Science Foundation of China[91753207] ; National Key R&D Program of China[2018YFA0508200] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Lingang Laboratory[LG202103-02-08]
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:000810724600003
源URL[http://119.78.100.183/handle/2S10ELR8/301536]  
专题新药研究国家重点实验室
通讯作者Xu, Yungen; Xie, Zuoquan; Zhou, Bing
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Bohai Rim Adv Res Inst Drug Discovery, PR China Shandong Lab Yantai Drug Discovery f, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.China Pharmaceut Univ, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 211198, Peoples R China
推荐引用方式
GB/T 7714		 Niu, Jing,Bai, Hudagula,Li, Zizhou,et al. Discovery of novel Thieno[2,3-d]imidazole derivatives as agonists of human STING for antitumor immunotherapy using systemic administration[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,238:16.
APA Niu, Jing.,Bai, Hudagula.,Li, Zizhou.,Gao, Yuzhe.,Zhang, Yan.,...&Zhou, Bing.(2022).Discovery of novel Thieno[2,3-d]imidazole derivatives as agonists of human STING for antitumor immunotherapy using systemic administration.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,238,16.
MLA Niu, Jing,et al."Discovery of novel Thieno[2,3-d]imidazole derivatives as agonists of human STING for antitumor immunotherapy using systemic administration".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 238(2022):16.

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。