Journal Article

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

Imaeda, Toshihiro, Lama, Lodoe, Steinberg, Joshua I., Kuryavyi, Vitaly, Aida, Jumpei, Stamford, Andrew, Tomita, Daisuke, Adura, Carolina, Glickman, J. Fraser, Ramos-Espiritu, Lavoisier, Meinke, Peter, Tuschl, Thomas, Asano, Yasutomi, Xie, Wei, Jennings, Andy J., Michino, Mayako, Kamei, Taku, Hashizume, Shogo, Okamoto, Rei, Kuroita, Takanobu, Gogakos, Tasos, Miller, Michael, Patel, Dinshaw J., Gao, Pu

2019

Overview

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. Cyclic GMP-AMP synthase (cGAS) is involved in the modulation of inflammatory responses. Here, the authors present small-molecule inhibitors of human cGAS, characterize their interaction with the protein, and show that the compounds are active in interferon-producing cells including primary human macrophages.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 49 / 49/90 / 49/98 / 631/154/1435/2163 / 631/250/262/2106 / 82/83 / AMP / Autoimmune Diseases - drug therapy / Autoimmune Diseases - immunology / Autoimmune Diseases - pathology / BASIC BIOLOGICAL SCIENCES / Cells, Cultured / Crystallography, X-Ray / Cyclic GMP / DNA - immunology / DNA - metabolism / Drug development / Drug Discovery - methods / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Guanosine triphosphate / High-throughput screening / High-Throughput Screening Assays - methods / Humanities and Social Sciences / Humans / Immunity, Innate - drug effects / Inflammatory diseases / Inhibitor drugs / Inhibitors / Interferon / Interferons - immunology / Interferons - metabolism / Lead compounds / Macrophages / Models, Molecular / multidisciplinary / Myeloid cells / Nucleotides, Cyclic - immunology / Nucleotides, Cyclic - metabolism / Nucleotidyltransferases - antagonists & inhibitors / Nucleotidyltransferases - immunology / Nucleotidyltransferases - isolation & purification / Nucleotidyltransferases - metabolism / Optimization / Organic chemistry / Pattern recognition receptors / Pharmacology / Primary Cell Culture / Recombinant Proteins - immunology / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Scaffolds / Science / Science (multidisciplinary)