2. Academic Validation
  3. Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid

Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid

  • J Med Chem. 2025 Mar 13;68(5):5471-5487. doi: 10.1021/acs.jmedchem.4c02665.
Guang-Hao Niu 1,  Wan-Chi Hsiao 2 3,  Po-Hsun Lee 2 3,  Li-Guo Zheng 4,  Yu-Shao Yang 5,  Wei-Cheng Huang 1,  Chih-Chien Hsieh 1,  Tai-Yu Chiu 1,  Jing-Ya Wang 1,  Ching-Ping Chen 1,  Chen-Lung Huang 1,  May-Su You 2,  Yi-Ping Kuo 5,  Chien-Ming Wang 2,  Zhi-Hong Wen 6,  Guann-Yi Yu 5,  Chiung-Tong Chen 1,  Ya-Hui Chi 1,  Chun-Wei Tung 1,  Shu-Ching Hsu 5,  Teng-Kuang Yeh 1,  Ping-Jyun Sung 4,  Mingzi M Zhang 2,  Lun Kelvin Tsou 1
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
  • 2 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
  • 3 Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan.
  • 4 National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan.
  • 5 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
  • 6 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan.
PMID: 40014799 DOI: 10.1021/acs.jmedchem.4c02665
Abstract

Pharmacological inhibition of the cGAS-STING-controlled innate immune pathway is an emerging therapeutic strategy for a myriad of inflammatory diseases. Here, we report GHN105 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, GHN105 dose-dependently inhibited cGAS-STING signaling and type I interferon responses in cells and in vivo. Moreover, orally administered GHN105 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 GHN105 serves as a safe, site-selective, and orally active covalent STING Inhibitor and devises a regimen that allows long-term systemic administration.

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