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Structure-activity relationship study of amidobenzimidazole derivatives as stimulator of interferon genes (STING) agonists
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-11-24 , DOI: 10.1016/j.ejmech.2022.114943
Xue Liu 1 , Mingjin Wang 1 , Minjian Yang 1 , Hanyu Sun 1 , Baolian Wang 1 , Xiandao Pan 1 , Xiaoguang Chen 1 , Jing Jin 1 , Xiaojian Wang 1
Affiliation  

Stimulator of interferon genes (STING) is a crucial adaptor protein that can regulate the innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, the activation of STING pathway is expected to be an efficacious immunotherapeutic tactic to treat cancer. In this study, we performed a structure-activity relationship study of amidobenzimidazole monomer, led to a series of ABZI STING agonist derivatives with potent STING-activating effects. Among them, compound 72, as a representative compound, markedly activated the STING-TBK1-IRF3 signaling pathway and significantly increased the mRNA and protein levels of IFN-β, CXCL10 and IL-6 in both WT THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). In addition, it was confirmed that compound 72 was highly selective for human STING, specifically targeting human STING signaling and showing no activation of m-STING.



中文翻译:

氨基苯并咪唑衍生物作为干扰素基因 (STING) 激动剂的构效关系研究

干扰素基因刺激物 (STING) 是一种重要的衔接蛋白,可在识别内源或外源 DNA 后,通过诱导 Ⅰ 型干扰素和其他细胞因子的分泌来调节先天免疫反应。由于 STING 在先天免疫系统中的关键作用,STING 通路的激活有望成为治疗癌症的有效免疫治疗策略。在这项研究中,我们对氨基苯并咪唑单体进行了结构-活性关系研究,得出了一系列具有强效 STING 激活作用的 ABZI STING 激动剂衍生物。其中化合物72作为代表化合物,显着激活STING-TBK1-IRF3信号通路,显着增加WT THP-1细胞和人外周血中IFN-β、CXCL10和IL-6的mRNA和蛋白水平单核细胞 (hPBMC)。

更新日期:2022-11-24
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