State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica , Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100050 , P. R. China.
Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica , Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100050 , P. R. China.
J Med Chem. 2020 Jan 9;63(1):260-282. doi: 10.1021/acs.jmedchem.9b01567. Epub 2019 Dec 20.
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.
干扰素基因刺激物（STING）是一种内质网定位的衔接蛋白（STING 受体），已被证明通过与天然环二核苷酸（CDN）配体结合而被激活，并在外源或内源性 DNA 的先天免疫感应中发挥重要作用，从而诱导 I 型干扰素和其他细胞因子。在本文中，我们描述了一系列对 STING 受体具有高活性的苯并咪唑酰胺 STING 激动剂，并提出了相关的结构-活性关系（SAR）。通过 STING 竞争结合测定测量了化合物 、 和 的相对效力。对 STING 信号通路的影响进行了更深入的研究，结果表明，三种化合物 、 和 显著增加了 IFN-β、CXCL10 和 IL-6 的蛋白水平和 mRNA 水平，而化合物 作为代表性化合物，可有效触发 STING、TBK1 和 IRF3 在人外周血单核细胞（hPBMCs）和 WT THP-1 细胞中的磷酸化。此外，化合物 在静脉给予建立的同源结肠肿瘤的小鼠中表现出令人印象深刻的抗肿瘤疗效。此外，还全面评估了化合物 的药代动力学特征。
