Abstract
A three-dimensional pharmacophore model was generated utilizing a set of known inhibitors of c-Myc-Max heterodimer formation. The model successfully identified a set of structurally diverse compounds with potential inhibitory activity against c-Myc. Nine compounds were tested in vitro, and four displayed affinities in the micromolar range and growth inhibitory activity against c-Myc-overexpressing cells. These studies demonstrate the applicability of pharmacophore modeling to the identification of novel and potentially more puissant inhibitors of the c-Myc oncoprotein.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Benzofurans / chemistry
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Benzofurans / pharmacology
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Cell Line
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Cell Proliferation / drug effects
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Circular Dichroism
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Electrophoretic Mobility Shift Assay
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Knockout Techniques
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HL-60 Cells
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HMGA1b Protein / biosynthesis
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HMGA1b Protein / genetics
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Humans
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Models, Molecular*
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Protein Binding
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Protein Multimerization
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Proto-Oncogene Proteins c-myc / chemistry*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Rats
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Benzofurans
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Proto-Oncogene Proteins c-myc
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Pyridines
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Pyrrolidines
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Thiazoles
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HMGA1b Protein