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. 2020 Jan 9;63(1):260-282.
doi: 10.1021/acs.jmedchem.9b01567. Epub 2019 Dec 20.

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

Qiumu Xi  1 , Mingjin Wang  1 , Wenqiang Jia  2 , Mingjian Yang  1 , Jinping Hu  1 , Jing Jin  1 , Xiaoguang Chen  1 , Dali Yin  1   2 , Xiaojian Wang  1   2
Affiliations

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

Qiumu Xi et al. J Med Chem. .

Abstract

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 16g, 24b, and 24e were measured by a STING competition binding assay. A more thorough study of the effect on the STING signaling pathway demonstrated that three compounds, 16g, 24b, and 24e, significantly increased the protein levels and mRNA levels of IFN-β, CXCL10, and IL-6, and 24b 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 24b demonstrated impressive antitumor efficacy in mice with established syngeneic colon tumors by intravenous administration. Furthermore, the pharmacokinetic profile of compound 24b was fully evaluated.

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