Abstract
Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1alpha. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxia-inducible genes critical for cancer progression. The observed effects are compound-specific and dose-dependent. Controlling gene expression with designed small molecules targeting the transcription factor-coactivator interface may represent a new approach for arresting tumor growth.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology*
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Angiogenesis Inhibitors / toxicity
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Binding, Competitive
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Cell Hypoxia
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Cell Line, Tumor
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Cell Survival / drug effects
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Diketopiperazines / chemical synthesis
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Diketopiperazines / chemistry
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Diketopiperazines / pharmacology*
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Diketopiperazines / toxicity
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Disulfides / chemical synthesis
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Disulfides / chemistry
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Disulfides / pharmacology*
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Disulfides / toxicity
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Dose-Response Relationship, Drug
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Gene Expression / drug effects
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Gene Expression Profiling
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Luciferases / genetics
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Models, Molecular
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Molecular Structure
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / prevention & control
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Oligonucleotide Array Sequence Analysis
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Protein Binding
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Vascular Endothelial Growth Factor A / biosynthesis
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p300-CBP Transcription Factors / antagonists & inhibitors*
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p300-CBP Transcription Factors / metabolism
Substances
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Angiogenesis Inhibitors
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Diketopiperazines
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Disulfides
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Luciferases
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p300-CBP Transcription Factors