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2018 ; 13
(4
): 1066-1081
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A High Content Screen in Macrophages Identifies Small Molecule Modulators of
STING-IRF3 and NFkB Signaling
#MMPMID29553248
Koch PD
; Miller HR
; Yu G
; Tallarico JA
; Sorger PK
; Wang Y
; Feng Y
; Thomas JR
; Ross NT
; Mitchison T
ACS Chem Biol
2018[Apr]; 13
(4
): 1066-1081
PMID29553248
show ga
We screened a library of bioactive small molecules for activators and inhibitors
of innate immune signaling through IRF3 and NFkB pathways with the goals of
advancing pathway understanding and discovering probes for immunology research.
We used high content screening to measure the translocation from the cytoplasm to
nucleus of IRF3 and NFkB in primary human macrophages; these transcription
factors play a critical role in the activation of STING and other
pro-inflammatory pathways. Our pathway activator screen yielded a diverse set of
hits that promoted nuclear translocation of IRF3 and/or NFkB, but the majority of
these compounds did not cause activation of downstream pathways. Screening for
antagonists of the STING pathway yielded multiple kinase inhibitors, some of
which inhibit kinases not previously known to regulate the activity of this
pathway. Structure-activity relationships (SARs) and subsequent chemical
proteomics experiments suggested that MAPKAPK5 (PRAK) is a kinase that regulates
IRF3 translocation in human macrophages. Our work establishes a high content
screening approach for measuring pro-inflammatory pathways in human macrophages
and identifies novel ways to inhibit such pathways; among the targets of the
screen are several molecules that may merit further development as
anti-inflammatory drugs.