Design, Synthesis,\nand Biological Evaluation of Amidobenzimidazole\nDerivatives as Stimulator of Interferon Genes (STING) Receptor Agonists

Stimulator of interferon genes (STING) is an endoplasmic\nreticulum-localized\nadaptor protein (STING receptor) that has been shown to be activated\nby binding to natural cyclic dinucleotide (CDN) ligands and plays\na vital role in innate immune sensing of exogenous or endogenous DNA,\nwhich then induces type I interferons and other cytokines. In this\npaper, we described a series of amidobenzimidazole STING agonists\nwith high potency for the STING receptor and presented the relevant\nstructure–activity relationships (SARs). The relative potencies\nof compounds <b>16g</b>, <b>24b</b>, and <b>24e</b> were measured by a STING competition binding assay. A more thorough\nstudy of the effect on the STING signaling pathway demonstrated that\nthree compounds, <b>16g</b>, <b>24b</b>, and <b>24e</b>, significantly increased the protein levels and mRNA levels of IFN-β,\nCXCL10, and IL-6, and <b>24b</b> as a representative compound\neffectively triggered the phosphorylation of STING, TBK1, and IRF3\nin both human peripheral blood mononuclear cells (hPBMCs) and WT THP-1\ncells. In addition, compound <b>24b</b> demonstrated impressive\nantitumor efficacy in mice with established syngeneic colon tumors\nby intravenous administration. Furthermore, the pharmacokinetic profile\nof compound <b>24b</b> was fully evaluated.