Molecular Diversity ( IF 3.9 ) Pub Date : 2023-10-05 , DOI: 10.1007/s11030-023-10736-1 Rongyao Zhou 1, 2 , Xiyuan Wang 3 , Deqiang Zhang 3 , Zhengsheng Zhan 1, 2, 4 , Wenhu Duan 1, 2, 4
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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：
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，位于内质网膜中。在被激动剂激活后，STING 触发 IRF 和 NF-κB 通路，产生 I 型干扰素和促炎细胞因子，最终引发先天免疫反应，实现有效的抗肿瘤疗效。我们设计合成了一系列苯并[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。提出的 12d/12e 和 STING 蛋白的结合模式表明，激动剂与 STING 蛋白的 CDN 结合域之间形成了两个经典的氢键、π-π 堆积相互作用以及π-阳离子相互作用。
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