Orally Bioavailable and Site-Selective Covalent STING Inhibitor 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 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.