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The\n DNA<\/jats:styled-content>\n \u2010activated type I\n IFN<\/jats:styled-content>\n pathway cyclic\n GMP<\/jats:styled-content>\n \u2010\n AMP<\/jats:styled-content>\n (\n cGAMP<\/jats:styled-content>\n ) synthase (\n cGAS<\/jats:styled-content>\n ) is linked to subsets of\n AGS<\/jats:styled-content>\n and lupus. This study was undertaken to identify inhibitors of the\n DNA<\/jats:styled-content>\n \u2013\n cGAS<\/jats:styled-content>\n interaction, and to test the lead candidate drug, X6, in a mouse model of AGS.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Trex1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice were treated orally from birth with either X6 or hydroxychloroquine (\n HCQ<\/jats:styled-content>\n ) for 8 weeks. Expression of\n IFN<\/jats:styled-content>\n \u2010stimulated genes (\n ISG<\/jats:styled-content>\n s) was quantified by quantitative polymerase chain reaction. Multiple reaction monitoring by ultra\u2010performance liquid chromatography coupled with tandem mass spectrometry was used to quantify the production of\n cGAMP<\/jats:styled-content>\n and X6 drug concentrations in the serum and heart tissue of\n Trex1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n On the basis of the efficacy\u2010to\u2010toxicity ratio established in\u00a0vitro, drug X6 was selected as the lead candidate for treatment of\n Trex1<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. X6 was significantly more effective than\n HCQ<\/jats:styled-content>\n in attenuating\n ISG<\/jats:styled-content>\n expression in mouse spleens (\n P<\/jats:italic>\n < 0.01 for\n Isg15<\/jats:italic>\n and\n Isg20<\/jats:italic>\n ) and hearts (\n P<\/jats:italic>\n < 0.05 for\n Isg15<\/jats:italic>\n ,\n Mx1<\/jats:italic>\n , and\n Ifnb,<\/jats:italic>\n and\n P<\/jats:italic>\n \u00a0< 0.01 for\n Cxcl10<\/jats:italic>\n ), and in reducing the production of\n cGAMP<\/jats:styled-content>\n in mouse heart tissue (\n P<\/jats:italic>\n < 0.05), thus demonstrating target engagement by the X6 compound. Of note, X6 was also more effective than\n HCQ<\/jats:styled-content>\n in reducing\n ISG<\/jats:styled-content>\n expression in\u00a0vitro (\n P<\/jats:italic>\n < 0.05 for\n \n IFI<\/jats:styled-content>\n 27\n <\/jats:italic>\n and\n \n MX<\/jats:styled-content>\n 1\n <\/jats:italic>\n , and\n P<\/jats:italic>\n < 0.01 for\n \n IFI<\/jats:styled-content>\n 44L\n <\/jats:italic>\n and\n \n PKR<\/jats:styled-content>\n <\/jats:italic>\n ) in human peripheral blood mononuclear cells from patients with\n SLE<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study demonstrates that X6 is superior to\n HCQ<\/jats:styled-content>\n for the treatment of an experimental autoimmune myocarditis mediated in\u00a0vivo by the\n cGAS<\/jats:styled-content>\n \/stimulator of\n IFN<\/jats:styled-content>\n genes (\n cGAS<\/jats:styled-content>\n \/\n STING<\/jats:styled-content>\n ) pathway. The findings suggest that drug X6 could be developed as a novel treatment for\n AGS<\/jats:styled-content>\n and\/or lupus to inhibit activation of the\n cGAS<\/jats:styled-content>\n \/\n STING<\/jats:styled-content>\n pathway.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.40559","type":"journal-article","created":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T04:30:30Z","timestamp":1526877030000},"page":"1807-1819","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":126,"title":["Inhibition of Cyclic\n GMP<\/scp>\n \u2010\n AMP<\/scp>\n Synthase Using a Novel Antimalarial Drug Derivative in\n Trex1<\/i>\n \u2010Deficient Mice"],"prefix":"10.1002","volume":"70","author":[{"given":"Jie","family":"An","sequence":"first","affiliation":[{"name":"University of Washington Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua 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