STING inhibitor SI-43 is a potent small molecule inhibitor of stimulator of interferon genes (STING) with IC50 of 0.11 uM against cGAMP-induced STING activation in THP1-Blue ISG cells.
SI-43 effectively inhibited cGAMP-induced release of IFN-β and CXCL-10 and blocked STING pathway signaling.
SI-43 induced proteasome-independent degradation of the SAVI-associated mutants STING S154 and STIN GM155, while sparing STING R232 and mSTING.
SI-43 binds to two coupled pockets of a STING dimer in its open conformation.
SI-43also able to inhibit STING activation induced by diABZI.
SI-43 shows low nanomolar inhibitory activity in THP1 cells harboring STINGR232, the wild-type STING with 60% of frequency in the human population.
SI-43 exhibits potent inhibition against cGAMP-induced mouse STING (mSTING) activation in THP1 cells (IC50 = 0.02-0.03 uM).
SI-43 (0.05–0.5 μM) significantly reduced IFN-β and CXCL-10 secretion in THP1 cells and bone marrow-derived macrophages (BMDM) isolated from mice, which is >10-fold more potent than SN-011.
SI-43 dramatically decreased cGAMP-induced phosphorylation of both STING and IRF3 in THP1-Blue ISG cells.
SI-43 (20 mg/kg PO, or 10 mg/kg, SC) demonstrated in vivo efficacy in cGAMP-induced autoimmune disease mouse model.