Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice

Jessica Vincent, Carolina Adura, Pu Gao, Antonio Luz, Lodoe Lama, Yasutomi Asano, Rei Okamoto, Toshihiro Imaeda, Jumpei Aida, Katherine Rothamel, Tasos Gogakos, Joshua Steinberg, Seth Reasoner, Kazuyoshi Aso, Thomas Tuschl, Dinshaw J. Patel (), J. Fraser Glickman () and Manuel Ascano ()
Additional contact information
Jessica Vincent: Vanderbilt University School of Medicine
Carolina Adura: The Rockefeller University
Pu Gao: Memorial Sloan-Kettering Cancer Center
Antonio Luz: The Rockefeller University
Lodoe Lama: The Rockefeller University
Yasutomi Asano: Tri-Institutional Therapeutics Discovery Institute
Rei Okamoto: Tri-Institutional Therapeutics Discovery Institute
Toshihiro Imaeda: Tri-Institutional Therapeutics Discovery Institute
Jumpei Aida: Tri-Institutional Therapeutics Discovery Institute
Katherine Rothamel: Vanderbilt University School of Medicine
Tasos Gogakos: The Rockefeller University
Joshua Steinberg: The Rockefeller University
Seth Reasoner: Vanderbilt University School of Medicine
Kazuyoshi Aso: Tri-Institutional Therapeutics Discovery Institute
Thomas Tuschl: The Rockefeller University
Dinshaw J. Patel: Memorial Sloan-Kettering Cancer Center
J. Fraser Glickman: The Rockefeller University
Manuel Ascano: Vanderbilt University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon binding double-stranded DNA, cyclic GMP-AMP synthase synthesizes a cyclic dinucleotide that initiates an inflammatory cellular response. Mouse studies that recapitulate causative mutations in the autoimmune disease Aicardi-Goutières syndrome demonstrate that ablating the cyclic GMP-AMP synthase gene abolishes the deleterious phenotype. Here, we report the discovery of a class of cyclic GMP-AMP synthase inhibitors identified by a high-throughput screen. These compounds possess defined structure-activity relationships and we present crystal structures of cyclic GMP-AMP synthase, double-stranded DNA, and inhibitors within the enzymatic active site. We find that a chemically improved member, RU.521, is active and selective in cellular assays of cyclic GMP-AMP synthase-mediated signaling and reduces constitutive expression of interferon in macrophages from a mouse model of Aicardi-Goutières syndrome. RU.521 will be useful toward understanding the biological roles of cyclic GMP-AMP synthase and can serve as a molecular scaffold for development of future autoimmune therapies.

Date: 2017
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DOI: 10.1038/s41467-017-00833-9

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