Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression

Lodoe Lama, Carolina Adura, Wei Xie, Daisuke Tomita (), Taku Kamei, Vitaly Kuryavyi, Tasos Gogakos, Joshua I. Steinberg, Michael Miller, Lavoisier Ramos-Espiritu, Yasutomi Asano, Shogo Hashizume, Jumpei Aida, Toshihiro Imaeda, Rei Okamoto, Andy J. Jennings, Mayako Michino, Takanobu Kuroita, Andrew Stamford, Pu Gao, Peter Meinke, J. Fraser Glickman (), Dinshaw J. Patel () and Thomas Tuschl ()
Additional contact information
Lodoe Lama: The Rockefeller University
Carolina Adura: The Rockefeller University
Wei Xie: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
Daisuke Tomita: Tri-Institutional Therapeutics Discovery Institute
Taku Kamei: Tri-Institutional Therapeutics Discovery Institute
Vitaly Kuryavyi: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
Tasos Gogakos: The Rockefeller University
Joshua I. Steinberg: The Rockefeller University
Michael Miller: Tri-Institutional Therapeutics Discovery Institute
Lavoisier Ramos-Espiritu: The Rockefeller University
Yasutomi Asano: Tri-Institutional Therapeutics Discovery Institute
Shogo Hashizume: Tri-Institutional Therapeutics Discovery Institute
Jumpei Aida: Tri-Institutional Therapeutics Discovery Institute
Toshihiro Imaeda: Tri-Institutional Therapeutics Discovery Institute
Rei Okamoto: Tri-Institutional Therapeutics Discovery Institute
Andy J. Jennings: Tri-Institutional Therapeutics Discovery Institute
Mayako Michino: Tri-Institutional Therapeutics Discovery Institute
Takanobu Kuroita: Tri-Institutional Therapeutics Discovery Institute
Andrew Stamford: Tri-Institutional Therapeutics Discovery Institute
Pu Gao: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
Peter Meinke: Tri-Institutional Therapeutics Discovery Institute
J. Fraser Glickman: The Rockefeller University
Dinshaw J. Patel: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
Thomas Tuschl: The Rockefeller University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.

Date: 2019
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DOI: 10.1038/s41467-019-08620-4

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