Zhou Peng, Yang Gen, Wang Yan, Peng Yaya, Xu Lingyun, Jiang Tao, Ma Jinliang, Dong Wenpei, Chen Chang-Po
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
Bioorg Med Chem. 2025 Aug 15;126:118216. doi: 10.1016/j.bmc.2025.118216. Epub 2025 Apr 27.
Constant activation of stimulator of interferon genes (STING), resulting from aberrant metabolism or mutations in STING1, can initiate inflammatory damage or autoimmune disease. STING antagonists have the potential to be used as therapeutics for inflammatory and autoimmune diseases. Based on the structures of the covalent STING inhibitor H151 and C178, we designed, synthesized, and evaluated a novel series of indole derivatives for STING inhibition. Several compounds exhibited efficacious STING inhibitory activity. One of these novel chemical entities, 4dc, was more potent than H151, with IC values of 0.14 μM in RAW-Lucia ISG cells and 0.39 μM in THP1-Dual™ cells. The compound effectively relieved the symptoms of renal injury in a cisplatin-induced acute kidney injury mouse model. Compound 4dc represents a new chemotype of STING inhibitor that deserves further investigation as anti-inflammatory agent.
由于异常代谢或干扰素基因刺激物（STING）1发生突变而导致的STING持续激活，可引发炎症损伤或自身免疫性疾病。STING拮抗剂有潜力用作治疗炎症和自身免疫性疾病的药物。基于共价STING抑制剂H151和C178的结构，我们设计、合成并评估了一系列用于抑制STING的新型吲哚衍生物。几种化合物表现出有效的STING抑制活性。这些新型化学实体之一4dc比H151更有效，在RAW-Lucia ISG细胞中的IC值为0.14μM，在THP1-Dual™细胞中的IC值为0.39μM。该化合物在顺铂诱导的急性肾损伤小鼠模型中有效缓解了肾损伤症状。化合物4dc代表了一种新型的STING抑制剂化学类型，作为抗炎剂值得进一步研究。
