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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of medicinal chemistry
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40014799/ |
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Table of Contents:
- Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid. Niu, Guang-Hao Hsiao, Wan-Chi Lee, Po-Hsun Zheng, Li-Guo Yang, Yu-Shao Huang, Wei-Cheng Hsieh, Chih-Chien Chiu, Tai-Yu Wang, Jing-Ya Chen, Ching-Ping Huang, Chen-Lung You, May-Su Kuo, Yi-Ping Wang, Chien-Ming Wen, Zhi-Hong Yu, Guann-Yi Chen, Chiung-Tong Chi, Ya-Hui Tung, Chun-Wei Hsu, Shu-Ching Yeh, Teng-Kuang Sung, Ping-Jyun Zhang, Mingzi M Tsou, Lun Kelvin Animals Diterpenes Humans Administration, Oral Membrane Proteins Mice Colitis Biological Availability Mice, Inbred C57BL Macrocyclic Compounds STING Protein Pharmacological inhibition of the cGAS-STING-controlled innate immune pathway is an emerging therapeutic strategy for a myriad of inflammatory diseases. Here, we report as an orally bioavailable covalent STING inhibitor. Late-stage diversification of the briarane-type diterpenoid excavatolide B allowed the installation of solubility-enhancing functional groups while enhancing its activity as a covalent STING inhibitor against multiple human STING variants, including the S154 variant responsible for a genetic autoimmune disease. Selectively engaging the membrane-proximal Cys91 residue of STING, dose-dependently inhibited cGAS-STING signaling and type I interferon responses in cells and in vivo. Moreover, orally administered exhibited on-target engagement in vivo and markedly reversed key pathological features in a delayed treatment of the acute colitis mouse model. Our study provided proof of concept that the synthetic briarane analog serves as a safe, site-selective, and orally active covalent STING inhibitor and devises a regimen that allows long-term systemic administration.