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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.

Authors:
 [1];  [1]; ORCiD logo [2];  [3];  [3];  [2];  [1];  [1];  [3];  [1];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [4] more »;  [3];  [1]; ORCiD logo [2];  [1] « less
  1. Rockefeller Univ., New York, NY (United States)
  2. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
  3. Tri-Institutional Therapeutics Discovery Inst., New York, NY (United States)
  4. Chinese Academy of Sciences (CAS), Beijing (China); Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Takeda Pharmaceutical Company; Memorial Sloan Kettering Cancer Center; The Rockefeller Univ., Weill Cornell Medicine
OSTI Identifier:
1524667
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 10; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; High-throughput screening; Pattern recognition receptors

Citation Formats

Lama, Lodoe, Adura, Carolina, Xie, Wei, Tomita, Daisuke, Kamei, Taku, Kuryavyi, Vitaly, Gogakos, Tasos, Steinberg, Joshua I., Miller, Michael, Ramos-Espiritu, Lavoisier, Asano, Yasutomi, Hashizume, Shogo, Aida, Jumpei, Imaeda, Toshihiro, Okamoto, Rei, Jennings, Andy J., Michino, Mayako, Kuroita, Takanobu, Stamford, Andrew, Gao, Pu, Meinke, Peter, Glickman, J. Fraser, Patel, Dinshaw J., and Tuschl, Thomas. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. United States: N. p., 2019. Web. doi:10.1038/s41467-019-08620-4.
Lama, Lodoe, Adura, Carolina, Xie, Wei, Tomita, Daisuke, Kamei, Taku, Kuryavyi, Vitaly, Gogakos, Tasos, Steinberg, Joshua I., Miller, Michael, Ramos-Espiritu, Lavoisier, Asano, Yasutomi, Hashizume, Shogo, Aida, Jumpei, Imaeda, Toshihiro, Okamoto, Rei, Jennings, Andy J., Michino, Mayako, Kuroita, Takanobu, Stamford, Andrew, Gao, Pu, Meinke, Peter, Glickman, J. Fraser, Patel, Dinshaw J., & Tuschl, Thomas. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. United States. doi:10.1038/s41467-019-08620-4.
Lama, Lodoe, Adura, Carolina, Xie, Wei, Tomita, Daisuke, Kamei, Taku, Kuryavyi, Vitaly, Gogakos, Tasos, Steinberg, Joshua I., Miller, Michael, Ramos-Espiritu, Lavoisier, Asano, Yasutomi, Hashizume, Shogo, Aida, Jumpei, Imaeda, Toshihiro, Okamoto, Rei, Jennings, Andy J., Michino, Mayako, Kuroita, Takanobu, Stamford, Andrew, Gao, Pu, Meinke, Peter, Glickman, J. Fraser, Patel, Dinshaw J., and Tuschl, Thomas. Tue . "Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression". United States. doi:10.1038/s41467-019-08620-4. https://www.osti.gov/servlets/purl/1524667.
@article{osti_1524667,
title = {Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression},
author = {Lama, Lodoe and Adura, Carolina and Xie, Wei and Tomita, Daisuke and Kamei, Taku and Kuryavyi, Vitaly and Gogakos, Tasos and Steinberg, Joshua I. and Miller, Michael and Ramos-Espiritu, Lavoisier and Asano, Yasutomi and Hashizume, Shogo and Aida, Jumpei and Imaeda, Toshihiro and Okamoto, Rei and Jennings, Andy J. and Michino, Mayako and Kuroita, Takanobu and Stamford, Andrew and Gao, Pu and Meinke, Peter and Glickman, J. Fraser and Patel, Dinshaw J. and Tuschl, Thomas},
abstractNote = {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.},
doi = {10.1038/s41467-019-08620-4},
journal = {Nature Communications},
number = [1],
volume = [10],
place = {United States},
year = {2019},
month = {5}
}

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