Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid.

Area of Science:

• Immunology
• Pharmacology
• Medicinal Chemistry

Background:

• The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key component of the innate immune system.
• Dysregulation of the cGAS-STING pathway is implicated in various inflammatory and autoimmune diseases.
• Targeting this pathway offers a potential therapeutic avenue for treating these conditions.

Purpose of the Study:

• To develop and characterize GHN105, a novel, orally bioavailable covalent inhibitor of STING.
• To evaluate the efficacy of GHN105 in preclinical models of inflammatory disease.
• To establish GHN105 as a safe and effective therapeutic agent for modulating innate immune responses.

Main Methods:

• Synthesis and chemical modification of excavatolide B to create GHN105.
• In vitro assays to assess STING inhibition and downstream signaling.
• In vivo studies in mouse models to evaluate pharmacokinetic properties and therapeutic efficacy.
• Analysis of STING variants, including the S154 variant associated with autoimmune disease.

Main Results:

• GHN105 demonstrated enhanced activity as a covalent STING inhibitor against multiple human STING variants.
• The compound selectively engaged the Cys91 residue of STING, dose-dependently inhibiting cGAS-STING signaling and type I interferon responses.
• Oral administration of GHN105 resulted in on-target engagement and significant reversal of pathological features in an acute colitis mouse model.
• A regimen for long-term systemic administration of GHN105 was developed.

Conclusions:

• GHN105 is a safe, site-selective, and orally active covalent STING inhibitor.
• This synthetic briarane analog represents a promising therapeutic candidate for inflammatory diseases.
• The study provides proof of concept for targeting the cGAS-STING pathway with orally administered small molecules.