X6

https://onlinelibrary.wiley.com/doi/10.1002/art.40559

Inhibition of Cyclic GMP‐AMP Synthase Using a Novel Antimalarial Drug Derivative in Trex1‐Deficient Mice
Jie An PhD Joshua J. Woodward PhD Weinan Lai MD Mark Minie PhD Xizhang Sun PhD Lena Tanaka MS Jessica M. Snyder DVM Tomikazu Sasaki PhD Keith B. Elkon MD
First published: 21 May 2018 https://doi.org/10.1002/art.40559
Supported by the Life Sciences Discovery Fund (grant 15834191), the Alliance for Lupus Research (Rare Disease Foundation Microgrant), and the University of Washington Innovation Fund. Research in Dr. Woodward’s laboratory is supported by the Pew Charitable Trust (Biomedical Scholarship). Dr. Lai’s work was supported by the Nanfang Hospital Science Foundation of China (grant 2014C008) and the Natural Science Foundation of Guangdong Province (grant 2017A030313508).
Drs. An, Woodward, Minie, Sasaki, and Elkon have a patent pending on the compounds X5–X7 described in this study.
Read the full text
ePDFPDFTOOLS SHARE
Abstract
Objective
Type I interferon (IFN) is strongly implicated in the pathogenesis of systemic lupus erythematosus (SLE) as well as rare monogenic interferonopathies such as Aicardi‐Goutières syndrome (AGS), a disease attributed to mutations in the DNA exonuclease TREX1. The DNA‐activated type I IFN pathway cyclic GMP‐AMP (cGAMP) synthase (cGAS) is linked to subsets of AGS and lupus. This study was undertaken to identify inhibitors of the DNA–cGAS interaction, and to test the lead candidate drug, X6, in a mouse model of AGS.

Methods
Trex1−/− mice were treated orally from birth with either X6 or hydroxychloroquine (HCQ) for 8 weeks. Expression of IFN‐stimulated genes (ISGs) was quantified by quantitative polymerase chain reaction. Multiple reaction monitoring by ultra‐performance liquid chromatography coupled with tandem mass spectrometry was used to quantify the production of cGAMP and X6 drug concentrations in the serum and heart tissue of Trex1−/− mice.

Results
On the basis of the efficacy‐to‐toxicity ratio established in vitro, drug X6 was selected as the lead candidate for treatment of Trex1−/− mice. X6 was significantly more effective than HCQ in attenuating ISG expression in mouse spleens (P < 0.01 for Isg15 and Isg20) and hearts (P < 0.05 for Isg15, Mx1, and Ifnb, and P < 0.01 for Cxcl10), and in reducing the production of cGAMP in mouse heart tissue (P < 0.05), thus demonstrating target engagement by the X6 compound. Of note, X6 was also more effective than HCQ in reducing ISG expression in vitro (P < 0.05 for IFI27 and MX1, and P < 0.01 for IFI44L and PKR) in human peripheral blood mononuclear cells from patients with SLE. Conclusion This study demonstrates that X6 is superior to HCQ for the treatment of an experimental autoimmune myocarditis mediated in vivo by the cGAS/stimulator of IFN genes (cGAS/STING) pathway. The findings suggest that drug X6 could be developed as a novel treatment for AGS and/or lupus to inhibit activation of the cGAS/STING pathway.