Orally Bioavailableand Site-Selective Covalent STINGInhibitor Derived from a Macrocyclic Marine Diterpenoid

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