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

doi:10.1016/j.ejmech.2022.114627

	Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists
	Shen, Ancheng 1,5; Li, Xiyuan2,3,4 ; Zhang, Yan 2; Ma, Jing 1; Xiao, Ruoxuan 1; Wang, Xiyuan 2; Song, Zilan 1; Liu, Zhiguo 5; Geng, Meiyu 2,4; Zhang, Ao 1,5; Xie, Zuoquan 2,4; Ding, Chunyong 1
	2022-11-05
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (IF:6.0[JCR-2023],6.1[5-Year])
ISSN	0223-5234
EISSN	1768-3254
卷号	241
发表状态	已发表
DOI	10.1016/j.ejmech.2022.114627
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.
关键词	Innate immunity STING Agonists Structural modification Immuno-oncology
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收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China["21877120","22177068","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","WF220217002","WH101117001","WF540162618"]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000879557200002
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/268657
专题	生命科学与技术学院_博士生
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.
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.
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).