Targeting STING oligomerization with small- molecule inhibitors

Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3-and NF kappa B- dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhib-itor of STING. This compound, BB- Cl-amidine inhibits STING signaling and pro-duction of type I IFNs, IFN-stimulated genes (ISGs) and NF kappa B-dependent cytokines, but not other pattern recognition receptors. In vivo, BB- Cl-amidine alleviated pathol-ogy resulting from accrual of cytosolic DNA in Trex- 1 mutant mice. Mechanistically BB- Cl-amidine inhibited STING oligomerization through modification of Cys148. Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases.