Development of indole derivatives as inhibitors targeting STING-dependent inflammation

Constant activation of stimulator of interferon genes (STING), resulting from aberrant metabolism or mutations in STING1, can initiate inflammatory damage or autoimmune disease. STING antagonists have the potential to be used as therapeutics for inflammatory and autoimmune diseases. Based on the structures of the covalent STING inhibitor H151 and C178, we designed, synthesized, and evaluated a novel series of indole derivatives for STING inhibition. Several compounds exhibited efficacious STING inhibitory activity. One of these novel chemical entities, 4dc, was more potent than H151, with IC₅₀ values of 0.14 μM in RAW-Lucia^TM ISG cells and 0.39 μM in THP1-Dual™ cells. The compound effectively relieved the symptoms of renal injury in a cisplatin-induced acute kidney injury mouse model. Compound 4dc represents a new chemotype of STING inhibitor that deserves further investigation as anti-inflammatory agent.