DDO-88109 is a potent small molecule STING inhibitor with SPR Kd of 317 nM for hSTING-CTDWT, shows broad affinity for hSTING isoforms (WT, HAQ, and H232) and selectively suppresses the activation of cGAS-STING signaling pathway.
DDO-88109 binds to CDN-binding pocket of the STING dimer, occupies the CDN-binding pocket of STING in a 2:1 stoichiometry, exhibiting Kd values of 3.02 and 0.97 µM, respectively in ITC assays.
DDO-88109 shows SPR Kd of 625 nM for mSTING-CTDWT.
DDO-88109 does not exhibit inhibitory effects on the enzymatic activity of human cGAS (h-cGAS) in luminescence-based enzymatic assays.
DDO-88109 maintains STING in an inactive state.
DDO-88109 exhibits broad-affinity to STING variants encoded by various alleles, shows concentration-dependent binding to the AQ and H232 isoforms of STING-CTD, with SPR Kd values of 698 nM and 960 nM, respectively.
DDO-88109 concentration-dependently suppresses cGAMP-induced IFNB transcription in STING (WT, HAQ, or H232)-transfected HEK293T cells.
DDO-88109 selectively suppresses cGAS-STING pathway signal transduction, down-regulates the transcriptional levels of IFNB and CXCL10 stimulated by cGAMP in THP1 cells.
DDO-88109 reduces the transcription of IFNB induced by cGAS agonist (ISD, HT-DNA), cyclic dinucleotide (CDN) STING agonist (CDG, cGAMP) and non-CDN small molecule STING agonist (diABZI, SR-717) in PMA-induced THP1-derived macrophages.
DDO-88109 inhibits cGAMP-induced phosphorylation of IRF3, p65, TBK1, and STING in a concentration-dependent manner in THP1 cells, also effectively blocks STING oligomerization and IRF3 dimerization.
DDO-88109 concentration-dependently inhibits the activation of the cGAS-STING pathway with IC50 of 1.76 μM and 1.85 μM in THP1-Dual and RAW-Lucia ISG cells, respectively.
DDO-88109 effectively alleviates systemic inflammation in Trex1 KO mice, significantly suppresses the transcription of Ifnb, Cxcl10, and Isg15, also effectively downregulates the transcriptional levels of inflammation-related genes in cardiac and renal tissues.
DDO-88109 ameliorates renal inflammation in cisplatin-induced acute kidney injury (AKI) mice, protects AKI mice from death via inhibition of the cGAS-STING-NF-κB pathway signaling.