Abstract
Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i)=13 μM), inhibited Stat3-Stat3 protein interactions (IC(50)=19 μM) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50)=10 and 16 μM, respectively).
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Membrane Permeability / drug effects*
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor
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Humans
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Ligands
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Models, Molecular
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Molecular Structure
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Molecular Weight
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / metabolism
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Salicylic Acid / chemical synthesis
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Salicylic Acid / chemistry
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Salicylic Acid / pharmacology*
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Small Molecule Libraries
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Stereoisomerism
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Structure-Activity Relationship
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src Homology Domains / drug effects*
Substances
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Antineoplastic Agents
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Ligands
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STAT3 Transcription Factor
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STAT3 protein, human
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Small Molecule Libraries
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Salicylic Acid