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

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 <b>6</b> (H-151) based on its potential metabolic hotspots. Compound <b>66</b>, 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 <b>66</b> engaged with STING in a covalent manner akin to that of <b>6</b>. In both the cisplatin-induced acute kidney injury and TREX1 D18N mouse models, <b>66</b> significantly alleviated tissue injury and inflammation.