Anti-inflammatory Activity of a Systemic STING Inhibitory Non-Nucleotide

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PROJECT SUMMARY Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved to detect microbial infection of the cell. STING controls the potent cytosolic DNA-stimulated innate immune pathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted by intracellular bacteria following infection. Alternatively, STING can be activated by cyclic GMP-AMP (cGAMP) generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNA species, which can include microbial DNA or self-DNA leaked from the nucleus. Association with CDNs enables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, which facilitate adaptive immunity. The activation of STING is critical for protection against microbial infection and cancer. However, chronic STING activation is a leading cause of autoinflammatory disease such as severe systemic lupus erythematosus (SLE), STING associated vasculopathy with onset in infancy (SAVI) inflammation of the gut, tissue transplant rejection and others. Here, we describe a new generation of novel small STING antagonists that inhibit STING signaling, for evaluation as anti-inflammatory therapeutic agents. The compounds have been generated by STINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.