COMPOUND 1 is a first-in-class small molecule cGAMP competitive oral STING antagonist that reduces lung inflammation and fibrosis in chronic bleomycin and silica mouse models

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Abstract Background: STING activation by cGAMP leads to canonical Type I IFN responses and non-canonical signaling that increase inflammation, pyroptosis, autophagy, senescence and fibrosis in conditions such as Idiopathic Pulmonary Fibrosis. COMPOUND 1 is a novel cGAMP competitive synthetic small molecule STING antagonist discovered at Curadev. Materials and Methods: Competitive binding was established using radioligand binding assays. Anti-fibrotic activity was established in Bleomycin and Silica induced lung fibrosis models in mice. PK and safety studies were evaluated in rodents. Results: COMPOUND 1 inhibits the binding of cGAMP to STING and causes reductions in the level of Type I interferons and pro-inflammatory cytokines from immune cells as well as in mice treated with a STING agonist. Once a day oral administration of COMPOUND 1 that commenced one week after intratracheal injury with bleomycin or silica in C57/Bl6 mice ameliorated lung inflammation and fibrosis with concomitant decreases in collagen load and inflammatory cytokines. Orally administration of the compound was well tolerated at high doses in a 14-day non-GLP rat safety study. Conclusions: COMPOUND 1 is an orally administered novel first-in-class cGAMP competitive STING antagonist with promising single agent anti-inflammatory and anti-fibrotic activity in chronic lung injury models making it is well suited for IND directed studies.

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