Rational design of carbazole-based STING inhibitors for treating cGAS-STING pathway-driven inflammatory disorders

Stimulator of Interferon Genes (STING) is a pivotal adaptor protein in the innate immune pathway, and its aberrant activation is closely associated with the pathogenesis of autoimmune diseases. Although it has emerged as an attractive therapeutic target for inflammatory disorders, current STING inhibitors still face challenges including off-target toxicity and limited understanding of binding mechanism. Herein, through a Target & Cell-based cascade screening and rational design, DDO-88109 with a carbazole scaffold is identified as a STING inhibitor, with IC50 values of 1.76 μM and 1.85 μM in THP1-Dual and RAW-Lucia ISG cells, respectively. Moreover, DDO-88109 shows broad affinity for hSTING isoforms (WT, HAQ, and H232) and suppresses the activation of the cGAS-STING signaling pathway with favorable selectivity. Structurally, DDO-88109 occupies the CDN-binding pocket of STING in a 2:1 stoichiometry determined by co-crystal structure study. In TREX1 deficiency driven autoinflammation and cisplatin-induced AKI male mice models, treatment with DDO-88109 (15 mg/kg) significantly reduces the secretion of inflammatory factors and ameliorates tissue inflammation. Collectively, the discovery of DDO-88109 establishes a paradigm for structure-based rational drug development of STING inhibitors to provide potential small-molecule therapeutics against cGAS-STING signaling driven human autoimmune diseases. Here the authors identify a carbazole-scaffold inhibitor targeting the CDN-binding pocket of STING via rational design, establishing a paradigm for structure-based rational drug development of STING inhibitors. The inhibitor, DDO-88109, alleviates inflammation in male mouse models of Trex1 deletion driven autoinflammation and cisplatin induced acute kidney injury.