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

  • Nat Commun. 2026 Jun 2. doi: 10.1038/s41467-026-73774-x.
Hui Li  #  1  2  3 ,  Wei Zheng  #  1  2  3 ,  Wenjing Bian  #  2  4 ,  Mei Li  2  4 ,  Zhidan Fan  5 ,  Ziwen Feng  1  2  3 ,  Xiaoyan Liu  2  4 ,  Shiduo Zhang  1  2  3 ,  Haohao Lu  1  2  3 ,  Yinquan Huang  1  2  3 ,  Jiaqing Jia  1  2  3 ,  Yifan Zhang  1  2  3 ,  Linlin Li  1  2  3 ,  Chunchen Che  1  2  3 ,  Haiguo Yu  6 ,  Yibei Xiao  7  8 ,  Qidong You  9  10  11 ,  Xiaoli Xu  12  13  14
Affiliations
  • 1. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
  • 3. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 4. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 5. Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing, China.
  • 6. Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 7. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. [email protected].
  • 8. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China. [email protected].
  • 9. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China. [email protected].
  • 10. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. [email protected].
  • 11. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China. [email protected].
  • 12. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China. [email protected].
  • 13. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. [email protected].
  • 14. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 42230579 DOI: 10.1038/s41467-026-73774-x
Abstract

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.

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