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Nat Commun. 2019 May 21;10(1):2261. doi: 10.1038/s41467-019-08620-4.

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

Author information

1
Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, NY, 10065, USA.
2
High-Throughput and Spectroscopy Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
3
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
4
Tri-Institutional Therapeutics Discovery Institute, 413 East 69th Street 16th Floor, New York, NY, 10021, USA.
5
Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
6
High-Throughput and Spectroscopy Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA. fglickman@rockefeller.edu.
7
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. pateld@mskcc.org.
8
Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, NY, 10065, USA. ttuschl@rockefeller.edu.

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.

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