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Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents

文献类型：期刊论文

作者Shen, Ancheng2,3,6; Wang, Xiyuan1,5; Chen, Qingxuan3,6; Zhang, Yan1; Wang, Fang4; Li, Yuqiang9; Liu, Zhiguo2; Deng, Liufu3,6; Ouyang, Wanli9; Geng, Meiyu1,5,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-04-06
卷号68期号:8页码:8907-8932
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00580
英文摘要Given the critical role of STING in autoimmune and inflammatory disorders, the development of targeted small-molecule inhibitors has been a promising strategy for the treatment of these diseases. Nevertheless, the currently reported STING inhibitors suffer from limited structural diversity, species sensitivity, and poor activity; therefore, none are suitable for clinical investigation. Herein, we performed a structural modification campaign on the tool compound 6 (H-151) based on its potential metabolic hotspots. Compound 66, bearing a difluorobenzodioxol moiety, was identified as one of the most potent STING inhibitors with IC50 values of 116 and 96.3 nM for h- and m-STING, respectively. This compound exhibited a notable enhancement in metabolic properties, especially in terms of metabolic stability. A mechanism study verified that 66 engaged with STING in a covalent manner akin to that of 6. In both the cisplatin-induced acute kidney injury and TREX1 D18N mouse models, 66 significantly alleviated tissue injury and inflammation.
WOS关键词CYCLIC GMP-AMP ; IMMUNE ; ADAPTER ; AUTOIMMUNITY ; SENSOR ; LIGAND
资助项目National Natural Science Foundation of China[82173653] ; National Natural Science Foundation of China[82273767] ; National Natural Science Foundation of China[22494694] ; National Natural Science Foundation of China[82073073] ; National Natural Science Foundation of China[82122045] ; National Natural Science Foundation of China[ZJ2021-ZD-007] ; National Natural Science Foundation of China[Technology-2030] ; National Natural Science Foundation of China[2021ZD0204004] ; National Natural Science Foundation of China[2022YFF1203005] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[LG202103-02-08] ; Shanghai Zhangjiang National Independent Innovation of China[2020CXJQ02] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001461017400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/316947]  
专题新药研究国家重点实验室
通讯作者Song, Zilan; Xie, Zuoquan; Zhang, Ao
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China
3.Shanghai Jiao Tong Univ, State Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
4.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
7.Guangdong Med Univ, Dongguan Affiliated Hosp 1, Dongguan 523808, Peoples R China
8.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
9.Shanghai Artificial Intelligence Lab, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Shen, Ancheng,Wang, Xiyuan,Chen, Qingxuan,et al. Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(8):8907-8932.
APA Shen, Ancheng.,Wang, Xiyuan.,Chen, Qingxuan.,Zhang, Yan.,Wang, Fang.,...&Zhang, Ao.(2025).Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents.JOURNAL OF MEDICINAL CHEMISTRY,68(8),8907-8932.
MLA Shen, Ancheng,et al."Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents".JOURNAL OF MEDICINAL CHEMISTRY 68.8(2025):8907-8932.

入库方式： OAI收割

来源：上海药物研究所

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