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

  • Nat Commun. 2019 May 21;10(1):2261. doi: 10.1038/s41467-019-08620-4.
Lodoe Lama  1 ,  Carolina Adura  2 ,  Wei Xie  3 ,  Daisuke Tomita  4 ,  Taku Kamei  4 ,  Vitaly Kuryavyi  3 ,  Tasos Gogakos  1 ,  Joshua I Steinberg  1 ,  Michael Miller  4 ,  Lavoisier Ramos-Espiritu  2 ,  Yasutomi Asano  4 ,  Shogo Hashizume  4 ,  Jumpei Aida  4 ,  Toshihiro Imaeda  4 ,  Rei Okamoto  4 ,  Andy J Jennings  4 ,  Mayako Michino  4 ,  Takanobu Kuroita  4 ,  Andrew Stamford  4 ,  Pu Gao  3  5 ,  Peter Meinke  4 ,  J Fraser Glickman  6 ,  Dinshaw J Patel  7 ,  Thomas Tuschl  8
Affiliations
  • 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. [email protected].
  • 7. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 8. Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, NY, 10065, USA. [email protected].
PMID: 31113940 DOI: 10.1038/s41467-019-08620-4
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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