Structure-Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists

doi:10.1021/acs.jmedchem.0c01900

	Structure-Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists
	Song, Zilan 2,3,4; Wang, Xiyuan 2,5; Zhang, Yan 2,5; Gu, Wangting 2,3; Shen, Ancheng 2,3; Ding, Chunyong 3; Li, Han 2,4; Xiao, Ruoxuan 3; Geng, Meiyu 2,5; Xie, Zuoquan 2,5
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-02-11
卷号	64 期号:3 页码:1649-1669
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.0c01900
通讯作者	Xie, Zuoquan(zqxie@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要	Activation of the stimulator of interferon gene (STING) has emerged as an exciting immuno-oncology therapeutic strategy; however, the first-generation STING agonists, cyclic dinucleotide (CDN) analogues, have suffered from many disadvantages and failed in clinical trials. Therefore, non-CDN small-molecule STING agonists are urgently needed. In view of the unique structure of the high potency of dimeric amidobenzimidazole STING agonist 5, a structural elaboration was conducted by modifying several structural hotspots of this scaffold. Triazole 40 was identified as a new potent STING activator, possessing EC50 values of 0.24 and 39.51 mu M for h- and m-STING, respectively. This compound has a slightly better pharmacokinetic profile and is >20-fold more aqueously soluble than 5. It activated the STING signaling dramatically by directly binding and stabilizing all h-STING isoforms and m-STING. In vivo, intermittent administration of 40 was found to have significant antitumor efficacy with good tolerance in two mouse tumor models.
资助项目	Chinese NSF[81703327] ; Chinese NSF[81773565] ; Personalized MedicinesMolecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020366] ; Personalized MedicinesMolecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020226] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-11-021] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-017] ; Shanghai Jiao Tong University[AF1700037] ; Shanghai Jiao Tong University[WF220217002] ; Shanghai Pujiang Program[18PJD052]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000619743200021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295465]
专题	中国科学院上海药物研究所
通讯作者	Xie, Zuoquan; Zhang, Ao
作者单位	1.Zhengzhou Univ, State Key Lab Esophageal Canc Prevent & Treatment, Minist Educ China, Zhengzhou 450001, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai Key Lab Mol Engn Chiral Drugs, Shanghai 200240, Peoples R China 4.Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Song, Zilan,Wang, Xiyuan,Zhang, Yan,et al. Structure-Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(3):1649-1669.
APA	Song, Zilan.,Wang, Xiyuan.,Zhang, Yan.,Gu, Wangting.,Shen, Ancheng.,...&Zhang, Ao.(2021).Structure-Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists.JOURNAL OF MEDICINAL CHEMISTRY,64(3),1649-1669.
MLA	Song, Zilan,et al."Structure-Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists".JOURNAL OF MEDICINAL CHEMISTRY 64.3(2021):1649-1669.