BBI-10

STING (stimulator of interferon genes) is a key component of cGAS-STING pathway, which plays an important role in the activation of innate immunity. cGAS (cyclic GMP–AMP synthase) acts as a DNA sensor, detecting DNA from sources such as invading bacteria, viruses, and cellular debris that can arise from aging and tissue damage. Upon DNA binding, cGAS produces the secondary messenger molecule cGAMP (cyclic GMP-AMP), which binds to STING. STING then undergoes the post-translational modification called palmitoylation, which activates the recruitment of kinases that phosphorylate IRF3 and IκBα. Phosphorylated IRF3 leads to activation of the type I interferon response, while phosphorylated IκBα activates NFκB and increases the secretion of pro- inflammatory cytokines such as IL-6 and TNFα, resulting in inflammation. While the innate immune response is an important defense mechanism, a dysregulated type I interferon response and overproduction of pro-inflammatory cytokines also represents a driving cause for multiple autoimmune and inflammatory diseases. As such, targeting the cGAS-STING pathway may be a novel approach to treating these diseases. BBI-10 specifically targets the palmitoylation site of STING, which allows it to inhibit both wild-type STING and gain-of-function mutants without competing with cGAMP binding, thus deactivating downstream signaling through IRF3 and IκBα, and ultimately suppressing inflammation.

BBI-10 is a potential first-in-class, covalent, small molecule inhibitor of STING palmitoylation. While first-generation STING inhibitors target the cGAMP binding site, next-generation STING antagonists that inhibit palmitoylation, such as BBI-10, avoid competition for binding with cGAMP, and also have the potential to inhibit hyperactive mutants of STING.

In addition, in vitro studies show that BBI-10 more potently blocks the STING pathway compared to other known STING palmitoylation inhibitors, and that mice treated with BBI-10 demonstrate significant decreases in pro-inflammatory cytokine production following stimulation of STING.