STING is an important immune-associated protein that localizes in the endoplasmic reticulum membrane. Upon being activated by its agonists, STING triggers the IRF and NF-κB pathways, which generates type I interferons and proinflammatory cytokines, and ultimately primes the innate immune responses to achieve valid antitumor efficacy. We designed and synthesized a series of benzo[b]thiophene-2-carboxamide derivatives. Through STING-agonistic activity evaluation, compounds 12d and 12e exhibited marginal human STING-activating activities. Western blot analysis demonstrated that both 12d and 12e treatment increased the phosphorylation of the downstream signaling molecules (TBK1 and IRF3) of STING. The proposed binding mode of 12d/12e and STING protein displayed that two canonical hydrogen bonds, a π-π stacking interaction, as well as a π-cation interaction formed between the agonist and the CDN-binding domain of STING protein.

Graphical abstract

中文翻译：

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苯并[b]噻吩-2-甲酰胺衍生物的设计、合成和STING激动活性

STING 是一种重要的免疫相关蛋白，定位于内质网膜。被其激动剂激活后，STING 会触发 IRF 和 NF-κB 通路，从而产生 I 型干扰素和促炎细胞因子，并最终启动先天免疫反应以实现有效的抗肿瘤功效。我们设计并合成了一系列苯并[ b ]噻吩-2-甲酰胺衍生物。通过 STING 激动活性评估，化合物12d和12e表现出边缘的人类 STING 激活活性。Western blot 分析表明，12d和12e处理均增加了 STING 下游信号分子（TBK1 和 IRF3）的磷酸化。所提出的12d / 12e和STING蛋白的结合模式表明，激动剂和STING蛋白的CDN结合域之间形成了两个典型的氢键、 π-π堆积相互作用以及π-阳离子相互作用。

图形概要