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cGAS inhibitors act on the cyclic dinucleotide synthase that senses double-stranded DNA in the cytosol. Bound to DNA, the enzyme makes the second messenger 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) from ATP and GTP. In 2013 this pathway was shown to activate stimulator of interferon genes (STING) and type I interferon production. RU.521 and XQ2B inhibit cGAS directly, and RU.521 lowered interferon expression in macrophages from autoimmune mice. Many other products are ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors, such as Enpp-1-IN-2. ENPP1 hydrolyzes extracellular 2'3'-cGAMP, so these compounds protect the messenger rather than block its synthesis. The downstream receptor of 2'3'-cGAMP has its own category, STING.
