Discovery of STING antagonists targeting cGAS-STING pathway to alleviate IMQ-induced psoriasis-like dermatitis

作者：Zhixiong Zhang, Xian Wei, Qiang Huang, Zhonghua Shi, Xiaofeng Chen, Jialin Wu, Xin Wang, Jiaqi Li, Lantu Gou, Jinliang Yang · 发表于：European Journal of Pharmaceutical Sciences · 年份：2025 · DOI：10.1016/j.ejps.2025.107091 · 被引用次数：6 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Cytokine Signaling Pathways and Interactions

• Three novel human and mouse STING antagonists were identified in this study. • 2-Phenylisothiazol-3(2H)-one was identified as a scaffold of STING antagonists. • Compounds 85, 98, and 99 could alleviate IMQ-induced psoriasis-like dermatitis. • Antifungal compounds 98 and 99 were firstly reported as STING antagonists. • Compounds 98 and 99 have the potential ability to protect against fungal infections. • This study established a high-throughput screening system for STING antagonists. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is pivotal in the immune defense against infections and cancer. However, aberrant activation of this pathway can trigger autoimmune and inflammatory diseases by inducing excessive production of type I interferon (IFN) and pro-inflammatory cytokines. Inhibition of the aberrant activation of the cGAS-STING signaling pathway by targeting STING represents a novel therapeutic strategy for these autoimmune and inflammatory disorders. In this study, we discovered three novel STING antagonists based on surface plasmon resonance (SPR), differential scanning fluorimetry (DSF), and ISRE (interferon stimulated response element)-luciferase assays. The efficacy and pharmacological mechanisms of the three STING antagonists for treating imiquimod (IMQ)-induced psoriasis-like dermatitis by western blotting (WB), flow fluorescence, and immunostaining. The three STING antagonists exhibited pan-inhibitory activities on the a...