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


Authors: Lama, L.; Adura, C.; Xie, W.; Tomita, D.; Kamei, T.; Kuryavyi, V.; Gogakos, T.; Steinberg, J. I.; Miller, M.; Ramos-Espiritu, L.; Asano, Y.; Hashizume, S.; Aida, J.; Imaeda, T.; Okamoto, R.; Jennings, A. J.; Michino, M.; Kuroita, T.; Stamford, A.; Gao, P.; Meinke, P.; Glickman, J. F.; Patel, D. J.; Tuschl, T.
Article Title: Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression
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. © 2019, The Author(s).
Journal Title: Nature Communications
Volume: 10
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2019-05-21
Start Page: 2261
Language: English
DOI: 10.1038/s41467-019-08620-4
PROVIDER: scopus
PMCID: PMC6529454
PUBMED: 31113940
DOI/URL:
Notes: Source: Scopus
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  1. Dinshaw J Patel
    445 Patel
  2. Pu Gao
    12 Gao
  3. Wei Xie
    14 Xie