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<p>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 &amp; Cell-based cascade screening and rational design, DDO-88109 with a carbazole scaffold is identified as a STING inhibitor, with IC<sub>50</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月2日

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  • Hui Li,
  • Wei Zheng,
  • Wenjing Bian,
  • Mei Li,
  • Zhidan Fan,
  • Ziwen Feng,
  • Xiaoyan Liu,
  • Shiduo Zhang,
  • Haohao Lu,
  • Yinquan Huang,
  • Jiaqing Jia,
  • Yifan Zhang,
  • Linlin Li,
  • Chunchen Che,
  • Haiguo Yu,
  • Yibei Xiao,
  • Qidong You,
  • Xiaoli Xu

摘要

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.