Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid
Guang‐Hao Niu, Wan‐Chi Hsiao, Po-Hsun Lee, Li-Guo Zheng, Yu-Shao Yang, Wei‐Cheng Huang, Chih-Chien Hsieh, Tai‐Yu Chiu, Jingya Wang, Ching-Ping Chen, Chen‐Lung Huang, May‐Su You, Yi-Ping Kuo, Chien‐Min 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, Lun K. Tsou
Abstract
High Resolution Image Download MS PowerPoint Slide 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.