Abstract
Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation. This complex is regulated by the 4E-BPs, which compete with eIF4G for binding to eIF4E and which have tumor-suppressor activity. To pharmacologically mimic 4E-BP function we developed a high-throughput screening assay for identifying small-molecule inhibitors of the eIF4E/eIF4G interaction. The most potent compound identified, 4EGI-1, binds eIF4E, disrupts eIF4E/eIF4G association, and inhibits cap-dependent translation but not initiation factor-independent translation. While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells. 4EGI-1 inhibits cellular expression of oncogenic proteins encoded by weak mRNAs, exhibits activity against multiple cancer cell lines, and appears to have a preferential effect on transformed versus nontransformed cells. The identification of this compound provides a new tool for studying translational control and establishes a possible new strategy for cancer therapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / isolation & purification*
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Antineoplastic Agents / pharmacology*
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Drug Evaluation, Preclinical / methods
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Eukaryotic Initiation Factor-4E / drug effects*
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Eukaryotic Initiation Factor-4E / genetics
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Eukaryotic Initiation Factor-4E / metabolism
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Eukaryotic Initiation Factor-4G / drug effects*
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Eukaryotic Initiation Factor-4G / genetics
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Eukaryotic Initiation Factor-4G / metabolism
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Feedback, Physiological / drug effects
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Feedback, Physiological / physiology
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Fluorescence Polarization Immunoassay / methods
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Hydrazones
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Jurkat Cells
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Mice
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Models, Molecular
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Nitro Compounds / chemistry
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Nitro Compounds / isolation & purification*
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Nitro Compounds / pharmacology*
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Oncogenes / drug effects
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Oncogenes / genetics
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology
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Protein Binding / drug effects
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Protein Binding / genetics
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Protein Biosynthesis / drug effects
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Protein Biosynthesis / genetics
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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Thiazoles / chemistry
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Thiazoles / isolation & purification*
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Thiazoles / pharmacology*
Substances
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4EGI-1 compound
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Antineoplastic Agents
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Eukaryotic Initiation Factor-4E
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Eukaryotic Initiation Factor-4G
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Hydrazones
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Nitro Compounds
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Peptide Fragments
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RNA, Messenger
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Thiazoles