化学
体内
脂多糖
ATP合酶
药理学
铅化合物
生物化学
酶
体外
结构-活动关系
免疫学
生物
遗传学
作者
Jing Tan,Bing Wu,Tingting Chen,Fan Chen,Jiannan Zhao,Chaodong Xiong,Chen‐Guo Feng,Ruoxuan Xiao,Chunyong Ding,Wei Tang,Ao Zhang
标识
DOI:10.1021/acs.jmedchem.1c00398
摘要
The activation of cyclic GMP–AMP synthase (cGAS) by double-stranded DNA is implicated in the pathogenesis of many hyperinflammatory and autoimmune diseases, and the cGAS-targeting small molecule has emerged as a novel therapeutic strategy for treating these diseases. However, the currently reported cGAS inhibitors are far beyond maturity, barely demonstrating in vivo efficacy. Inspired by the structural novelty of compound 5 (G140), we conducted a structural optimization on both its side chain and the central tricyclic core, leading to several subseries of compounds, including those unexpectedly cyclized complex ones. Compound 25 bearing an N-glycylglycinoyl side chain was identified as the most potent one with cellular IC50 values of 1.38 and 11.4 μM for h- and m-cGAS, respectively. Mechanistic studies confirmed its direct targeting of cGAS. Further, compound 25 showed superior in vivo anti-inflammatory effects in the lipopolysaccharide-induced mouse model. The encouraging result of compound 25 provides solid evidence for further pursuit of cGAS-targeting inhibitors as a new anti-inflammatory treatment.
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