Guang-Hao Niu, Wan-Chi Hsiao, Po-Hsun Lee, Li-Guo Zheng, Yu-Shao Yang, Wei-Cheng Huang, Chih-Chien Hsieh, Tai-Yu Chiu, Jing-Ya Wang, Ching-Ping Chen, Chen-Lung Huang, May-Su You, Yi-Ping Kuo, Chien-Ming Wang, Zhi-Hong Wen, Guann-Yi Yu, Chiung-Tong Chen, Ya-Hui Chi, Chun-Wei Tung, Shu-Ching Hsu, Teng-Kuang Yeh, Ping-Jyun Sung, Mingzi M. Zhang, and Lun Kelvin Tsou
Journal of Medicinal Chemistry 2025
DOI: 10.1021/acs.jmedchem.4c02665
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.
