Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 11, Pages 7667-7690Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00398
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Funding
- Natural Science Foundation of China [81773565]
- Science and Technology Commission of Shanghai Municipality [18431907100]
- Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery [AF1700037, WF220217002]
- Shanghai Jiao Tong University [WH101117001]
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A study has identified compound 25 as a potent cGAS inhibitor with strong anti-inflammatory effects in vivo, supporting the pursuit of cGAS-targeting inhibitors as a new therapeutic approach for inflammatory and autoimmune diseases.
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 mu M 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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