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Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists

文献类型：期刊论文

作者Shen, Ancheng1,5; Li, Xiyuan2,3,4; Zhang, Yan2; Ma, Jing1; Xiao, Ruoxuan1; Wang, Xiyuan2; Song, Zilan1; Liu, Zhiguo5; Geng, Meiyu2,4; Zhang, Ao1,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-11-05
卷号241页码:16
ISSN号0223-5234
关键词Innate immunity STING Agonists Structural modification Immuno-oncology
DOI10.1016/j.ejmech.2022.114627
通讯作者Xie, Zuoquan(zqxie@simm.ac.cn) ; Ding, Chunyong(chunding@sjtu.edu.cn)
英文摘要Pharmacological activation of stimulator of interferon genes (STING) by agonists has emerged as a new modality of cancer immunotherapy. However, current available STING agonists remain in early developmental stage or failed in clinic trials due to limited efficacy in humans. In this report, we performed a structure-activity rela-tionship study based on the benzothiophene oxobutanoic acid scaffold of MSA-2, a well-documented STING agonist by Merck, leading to a series of N-substituted acyloxyamino derivatives with potent STING activating effect. Among them, compounds 57 and 60 displayed the most potent activity specifically targeting both h-and m-STING. Particularly, 57 displayed more potent and rapid activation of the STING signaling pathway than ADU-S100 in THP1-Dual cells. In vivo anti-tumor efficacy of 57 by intratumoral or oral administration was also demonstrated in several mouse tumor models. Intriguingly, treatment with 57 eradicated all the CT26 tumor without further recurrence in all treated mice, which could also reject the same tumor re-inoculation, indicating an induction of immune memory by 57. Taken together, acyloxyamino derivative 57 represents a new chemo-type of STING agonist with well-demonstrated in vivo anti-tumor activity, which is deserved for further investigation.
WOS关键词CELL CO-STIMULATION ; CYCLIC GMP-AMP ; IMMUNE ; IMMUNOTHERAPY ; ADAPTER
资助项目National Natural Science Foundation of China[21877120] ; National Natural Science Foundation of China[22177068] ; National Natural Science Foundation of China[81821005] ; Science and Technology Commission of Shanghai Municipality[21ZR1429100] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; Start-up grants to the Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery from Shanghai Jiao Tong University[AF1700037] ; Start-up grants to the Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery from Shanghai Jiao Tong University[WF220217002] ; Start-up grants to the Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery from Shanghai Jiao Tong University[WH101117001] ; Start-up grants to the Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery from Shanghai Jiao Tong University[WF540162618]
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:000879557200002
源URL[http://119.78.100.183/handle/2S10ELR8/304249]  
专题新药研究国家重点实验室
通讯作者Xie, Zuoquan; Ding, Chunyong
作者单位1.Shanghai Jiao Tong Univ, Pharm Ctr 10, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Wenzhou Med Univ, Sch Pharmaceut Sci, Univ Town 1210, Wenzhou 325035, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Shen, Ancheng,Li, Xiyuan,Zhang, Yan,et al. Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,241:16.
APA Shen, Ancheng.,Li, Xiyuan.,Zhang, Yan.,Ma, Jing.,Xiao, Ruoxuan.,...&Ding, Chunyong.(2022).Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,241,16.
MLA Shen, Ancheng,et al."Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 241(2022):16.

入库方式： OAI收割

来源：上海药物研究所

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