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Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor

文献类型：期刊论文

作者Li, Wenxin1; Wang, Xiyuan2; Zang, Shumin2,3; Zhou, Rongyao1; Zhou, Hongfei1,3; Yue, Hangtian1,2,4; Geng, Meiyu2,3,5; Zhan, Zhengsheng1,3; Xie, Zuoquan2,3; Duan, Wenhu1,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2026-01-05
卷号301页码:18
ISSN号0223-5234
DOI10.1016/j.ejmech.2025.118232
英文摘要Stimulator of interferon genes (STING) plays an imperative role in the innate immune response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Overstimulated STING axis has proven to incur multiple autoimmune or inflammatory diseases, such as Aicardi-Goutie`res syndrome, systematic lupus erythematosus, and amyotrophic lateral sclerosis. Here we report the discovery of a series of 3,3-dimethyl-2-oxoindo-line STING inhibitors. We converted the STING agonist G10 to a STING inhibitor 8a by grafting an indole-3-yl group, and extensive structure-activity relationship (SAR) exploration of 8a allowed us to identify compound 10a as a potent and orally bioavailable STING inhibitor. Biological characterization unraveled that 10a significantly suppressed the STING signaling pathway in human monocytes and murine macrophages, potently alleviated cisplatin-induced kidney injury both in vitro and in vivo, as well as achieved robust anti-inflammatory efficacy on STING agonist-induced inflammation mice model through systemic administration. The proposed binding mode of 10a and the STING protein displays that 10a targets the transmembrane domain of STING.
WOS关键词INNATE ; DNA ; RECOGNITION ; ACTIVATION ; LIGAND ; SENSOR ; AMP
资助项目Shanghai Institute of Materia Medica[SIMM0320231002] ; Shandong Laboratory Program[SYS202205]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001596631400001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/320744]  
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.Chinese Acad Sci, Shanghai Inst Mat Med, Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Li, Wenxin,Wang, Xiyuan,Zang, Shumin,et al. Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2026,301:18.
APA Li, Wenxin.,Wang, Xiyuan.,Zang, Shumin.,Zhou, Rongyao.,Zhou, Hongfei.,...&Duan, Wenhu.(2026).Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,301,18.
MLA Li, Wenxin,et al."Discovery of a potent and orally bioavailable 3,3-dimethyl-2-oxoindoline STING inhibitor".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 301(2026):18.

入库方式： OAI收割

来源：上海药物研究所

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