A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling

• DOI: 10.1021/acschembio.7b01060
• Publication Date: 2018-03-19T12:48:38Z
• Authors: Peter D. Koch; Howard R. Miller; Gary Yu; John A. Tallarico; Peter K. Sorger; Yuan Wang; Yan Feng; Jason R. Thomas; Nathan T. Ross; Timothy Mitchison
• Keywords: IRF3; Sting; High-Content Screening

We screened a library of bioactive small molecules for activators and inhibitors innate immune signaling through IRF3 NFkB pathways with the goals advancing pathway understanding discovering probes immunology research. used high content screening to measure translocation from cytoplasm nucleus in primary human macrophages; these transcription factors play critical role activation STING other pro-inflammatory pathways. Our activator screen yielded diverse set hits that promoted nuclear and/or NFkB, but majority compounds did not cause downstream Screening antagonists multiple kinase inhibitors, some which inhibit kinases previously known regulate activity this pathway. Structure–activity relationships (SARs) subsequent chemical proteomics experiments suggested MAPKAPK5 (PRAK) is regulates macrophages. work establishes approach measuring macrophages identifies novel ways such pathways; among targets are several may merit further development as anti-inflammatory drugs.