Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents
Ancheng Shen, Xiyuan Wang, Qingxuan Chen, Yan Zhang, Fang Wang, Yuqiang Li, Zhiguo Liu, Liufu Deng, Wanli Ouyang, Meiyu Geng, Zilan Song, Zuoquan Xie, Ao Zhang
Abstract
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 IC 50 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.