Development of STING inhibitors with indole and pyrazine derivatives linked through amide bond as potent anti-inflammatory agents.

The essential role of STING-mediated signaling in autoimmune and inflammatory disorders makes it a compelling therapeutic target, driving the development of novel small-molecule STING inhibitors. Based on the lead STING inhibitor H151, herein we designed and prepared a series of novel STING inhibitors composed of amino indole and pyrazine derivatives linked with amide bond. Structure activity relationship investigation demonstrated that compound QQ21 showed significant improved STING inhibition activity in mouse RAW-Lucia™ ISG cells with an IC50 value of 86 nM, which is 8-fold of the efficacy of H151. QQ21 effectively inhibited the activity of STING agonist CMA in mouse. In cisplatin-induced acute kidney injury (AKI) mouse model, QQ21 significantly prevented kidney function damage and inflammation.