HCS campaign to identify selective inhibitors of IL-6-induced STAT3 pathway activation in head and neck cancer cell lines

Assay and Drug Development Technologies
Paul A JohnstonJennifer Grandis

Abstract

Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dep...Continue Reading

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Citations

Jan 24, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Suqing LiuYunyan Sun
Mar 15, 2016·Expert Opinion on Drug Discovery·Ivan Fraietta, Fabio Gasparri
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Oct 10, 2019·Epigenetics : Official Journal of the DNA Methylation Society·Malabika SenJames G Herman
Jul 8, 2017·Journal of Chemical Biology·Malabika SenJennifer R Grandis

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Methods Mentioned

BETA
biopsies
surgical resection
Assay
xenograft
294 assay
xenografts

Software Mentioned

XLfit
Topomer
MLSCN
[UNK]
TE
CytoMiner
GraphPad Prism

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