Discovery of Small-Molecule Cyclic GMP-AMP Synthase Inhibitors

Rosaura Padilla-Salinas, Lijun Sun, Rachel Anderson, Xikang Yang, Shuting Zhang, Zhijian J. Chen, Hang Yin

Research output: Contribution to journalArticle

Abstract

Cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) (cGAS), a cytosolic DNA sensor, plays an important role in the type I interferon response. DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS. Aberrant activation of cGAS is associated with various autoimmune disorders. Only one selective probe exists for inhibiting cGAS in cells, while others are limited by their poor cellular activity or specificity, which underscores the urgency for discovering new cGAS inhibitors. Here, we describe the development of new small-molecule human cGAS (hcGAS) inhibitors (80 compounds synthesized) with high binding affinity in vitro and cellular activity. Our studies show CU-32 and CU-76 selectively inhibit the DNA pathway in human cells but have no effect on the RIG-I-MAVS or Toll-like receptor pathways. CU-32 and CU-76 represent a new class of hcGAS inhibitors with activity in cells and provide a new chemical scaffold for designing probes to study cGAS function and development of autoimmune therapeutics.

Original languageEnglish (US)
Pages (from-to)1579-1600
Number of pages22
JournalJournal of Organic Chemistry
Volume85
Issue number3
DOIs
StatePublished - Feb 7 2020

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint Dive into the research topics of 'Discovery of Small-Molecule Cyclic GMP-AMP Synthase Inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Padilla-Salinas, R., Sun, L., Anderson, R., Yang, X., Zhang, S., Chen, Z. J., & Yin, H. (2020). Discovery of Small-Molecule Cyclic GMP-AMP Synthase Inhibitors. Journal of Organic Chemistry, 85(3), 1579-1600. https://doi.org/10.1021/acs.joc.9b02666