DDO-6513 is a specific molecular glue that induces aberrant STING oligomerization, inhibits STING activity with IC50 of 1.93 uM in IRF luciferase reporter assays in THP-1-Dual cells and ITC Kd of 151 nM, binds to the wing region of butterfly-shaped LBDs of STING, specifically inhibits human STING activation.
DDO-6513 induces self-association of STING.
DDO-6513 (20 uM) induces the formation of STING puncta, independent of the Golgi apparatus, and inhibits the translocation of STING from the ER to the Golgi upon cGAMP stimulation in GFP-STING-reconstituted HeLa cells and WI-38 cells.
DDO-6513 specifically inhibits STING-dependent signal transduction, inhibits the IFN gene signature and immune response.
DDO-6513 has inhibitory effects on multiple STING subtypes and is a broad-spectrum STING inhibitor, has no effect on STING mRNA levels.
DDO-6513 is a specific inhibitor of the STING-dependent TBK1-IRF3 signaling pathway.
DDO-6513 ameliorates pathological human STING overactivation, attenuates the expression of ISGs (MX1, IFNB1 and ISG56) and TNFA in PBMCs from an AGS patient carrying TREX1 mutations that led to excessive activation of the STING pathway.