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Discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents

文献类型：期刊论文

作者Zhou, Xiaoqian2,4,5; Yue, Hangtian3,6; Wang, Xiyuan3; Zang, Shumin3,7; Li, Han3,4,6; Yao, Shanyan2; Geng, Meiyu1,3,6,7; Zhan, Zhengsheng2,7; Xie, Zuoquan3,7; Duan, Wenhu2,7
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-11-05
卷号297页码:20
关键词Stimulator of interferon genes Inhibitors Acute kidney injury 3,4-Dihydroisoquinoline-2(1H)-Carboxamide
ISSN号0223-5234
DOI10.1016/j.ejmech.2025.117922
英文摘要Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein that plays a vital role in mediating the cytosolic DNA-sensing pathway to prime the innate immune responses. Overactivated STING axis causes excessive accumulation of interferons and proinflammatory cytokines, leading to autoimmune and autoinflammatory diseases such as STING-associated vasculopathy of infancy (SAVI) and Aicardi-Goutie`res syndrome (AGS). Inhibiting the aberrant STING signaling with its inhibitors has proven to alleviate the inflammatory symptoms of the autoimmune and autoinflammatory diseases. Here we report the discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors. Extensive structure-activity relationship (SAR) study allowed us to identify compound 5c with cellular human-and mouse-STING inhibitory IC50 values of 44 and 32 nM, respectively. It effectively inhibited the activation of the STING axis in both human and murine cells, potentially through covalent binding to the transmembrane domain of STING. Compound 5c also demonstrated robust in vivo anti-inflammatory efficacy on STING agonist-stimulated systemic inflammation and cisplatininduced acute kidney injury (AKI) mice models. Further study revealed that 5c could restore renal mitochondrial function, suppress reactive oxygen species production, and reduce cell apoptosis to protect mice against cisplatin-induced AKI.
WOS关键词ACTIVATION ; LIGAND ; TREX1 ; GMP
资助项目Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231002] ; Shandong Laboratory Program[SYS202205]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001527186500001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/318816]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Zhan, Zhengsheng; Xie, Zuoquan; Duan, Wenhu
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, Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Lingang Lab, Shanghai 200031, Peoples R China
5.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Xiaoqian,Yue, Hangtian,Wang, Xiyuan,et al. Discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,297:20.
APA Zhou, Xiaoqian.,Yue, Hangtian.,Wang, Xiyuan.,Zang, Shumin.,Li, Han.,...&Duan, Wenhu.(2025).Discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,297,20.
MLA Zhou, Xiaoqian,et al."Discovery of 3,4-dihydroisoquinoline-2(1H)-carboxamide STING inhibitors as anti-inflammatory agents".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 297(2025):20.

入库方式： OAI收割

来源：上海药物研究所

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