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A molecular glue induces aberrant STING oligomerization and inhibits autoinflammatory diseases.

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Τίτλος: A molecular glue induces aberrant STING oligomerization and inhibits autoinflammatory diseases.
Συγγραφείς: Feng ZW; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Zeng T; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Shu Q; Department of Pharmacy, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China., Li XZ; Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, China., Yu HG; Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing, China., Dai W; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Liu XC; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Tian XJ; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Xu F; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Li H; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Zhou YL; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Zhang SD; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Li LL; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Chen NN; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Liu XY; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Liu ZW; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Yin J; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Shen HT; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Che CC; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Chen MR; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China., Wang DD; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China., Sun LY; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China. lingyunsun@nju.edu.cn., Xiao YB; State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, China. yibei.xiao@cpu.edu.cn.; Chongqing Innovation Institute, China Pharmaceutical University, Chongqing, China. yibei.xiao@cpu.edu.cn., You QD; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. youqd@163.com.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China. youqd@163.com., Xu XL; Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. xuxiao_li@126.com.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China. xuxiao_li@126.com.
Πηγή: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2026 Aug 04; Vol. 11 (1). Date of Electronic Publication: 2026 Aug 04.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101676423 Publication Model: Electronic Cited Medium: Internet ISSN: 2059-3635 (Electronic) Linking ISSN: 20593635 NLM ISO Abbreviation: Signal Transduct Target Ther Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Publishing Group, [2016]-
Ιατρικοί όροι (MeSH): Membrane Proteins*/genetics , Membrane Proteins*/chemistry , Membrane Proteins*/antagonists & inhibitors , Autoimmune Diseases*/genetics , Autoimmune Diseases*/drug therapy , Autoimmune Diseases*/pathology , Protein Multimerization*/drug effects , Protein Multimerization*/genetics , Inflammation*/genetics , Inflammation*/drug therapy , Inflammation*/pathology, Herpesvirus 1, Human/genetics ; Herpesvirus 1, Human/pathogenicity ; Interferon Type I/genetics ; STING Protein ; Humans ; Animals ; Mice ; cGAS-STING Signaling Pathway
Περίληψη: Dysregulated activation of the stimulator of interferon genes (STING) pathway underlies various inflammatory and autoimmune pathologies. Since STING oligomerization is fundamental to its biological function, targeted modulation of this polymerization process presents a promising therapeutic approach. However, achieving precise control over STING polymerization has remained a significant challenge. In this study, we report that benzofuran derivatives serve as molecular glues to potently inhibit STING activity by inducing its aberrant oligomerization. Structural analyses demonstrated that these compounds function as glues, promoting an unconventional "head-to-head" STING dimerization configuration that differs markedly from the linear polymers formed during canonical pathway activation. These compounds exhibit potent inhibitory activity against different STING isoforms activated by 2',3'-cGAMP, dsDNA, gain-of-function SAVI-associated STING mutant, and herpes simplex virus type 1 (HSV-1) infection. DDO-6513 downregulates the expression of type I interferons (IFN-I), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines in clinical samples isolated from patients with STING-associated autoimmune disorders, including Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), and dermatomyositis (DM). In vivo, DDO-7432 displays desirable drug-like properties, and exerts remarkable anti-inflammatory efficacy in murine myositis disease models. Our findings demonstrate that modulating protein oligomerization via molecular glues can effectively disrupt signal transduction, providing novel insights into therapeutic strategies for oligomerization-dependent targets.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare the following competing interests: X.X., Q.D., Y.X., Z.F., X.T., F.X., and W.D. are inventors on patent applications related to STING inhibitors. All the other authors declare that they have no competing interests.
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Substance Nomenclature: 0 (STING Protein)
0 (Membrane Proteins)
0 (STING1 protein, human)
0 (Interferon Type I)
Entry Date(s): Date Created: 20260804 Date Completed: 20260804 Latest Revision: 20260813
Update Code: 20260814
PubMed Central ID: PMC13433806
DOI: 10.1038/s41392-026-02863-6
PMID: 42547770
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2059-3635
DOI:10.1038/s41392-026-02863-6