Design, Synthesis, and Biological Evaluation of Amidobenzimidazole Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein (STING receptor) that has been shown to be activated by binding to natural cyclic dinucleotide (CDN) ligands and plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). The relative potencies of compounds , , and were measured by a STING competition binding assay. A more thorough study of the effect on the STING signaling pathway demonstrated that three compounds, , , and , significantly increased the protein levels and mRNA levels of IFN-β, CXCL10, and IL-6, and as a representative compound effectively triggered the phosphorylation of STING, TBK1, and IRF3 in both human peripheral blood mononuclear cells (hPBMCs) and WT THP-1 cells. In addition, compound demonstrated impressive antitumor efficacy in mice with established syngeneic colon tumors by intravenous administration. Furthermore, the pharmacokinetic profile of compound was fully evaluated.