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
  • 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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