Abstract
The mammalian target of rapamycin (mTOR) signaling network is central to the regulation of cell growth in response to both growth factors and nutrients. We developed a high-throughput, cell-based assay to identify small-molecule modulators of the mTOR signaling network. One such compound, which we name quinostatin, potently inhibits this network by directly targeting the lipid-kinase activity of the catalytic subunits of class Ia PI3Ks. This study illustrates the power of unbiased, phenotypic screening as a means for illuminating cell circuitry, and resulted in the identification of a chemotype for selective inhibition of the class Ia PI3Ks.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Catalytic Domain
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Cell Line, Tumor
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / isolation & purification*
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Humans
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation / drug effects
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Protein Kinases / metabolism
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Quinolines / chemistry
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Quinolines / isolation & purification*
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Quinolines / pharmacology*
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Ribosomal Protein S6 / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases
Substances
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Heterocyclic Compounds, 3-Ring
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Phosphoinositide-3 Kinase Inhibitors
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Quinolines
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Ribosomal Protein S6
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quinostatin
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Protein Kinases
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MTOR protein, human
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases