Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine.
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.
Mesh Terms:
Angiogenesis Inhibitors, Binding, Competitive, Cell Hypoxia, Cell Line, Tumor, Cell Survival, Diketopiperazines, Disulfides, Dose-Response Relationship, Drug, Gene Expression, Gene Expression Profiling, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Luciferases, Models, Molecular, Molecular Structure, Neovascularization, Pathologic, Oligonucleotide Array Sequence Analysis, Protein Binding, Vascular Endothelial Growth Factor A, p300-CBP Transcription Factors
Angiogenesis Inhibitors, Binding, Competitive, Cell Hypoxia, Cell Line, Tumor, Cell Survival, Diketopiperazines, Disulfides, Dose-Response Relationship, Drug, Gene Expression, Gene Expression Profiling, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Luciferases, Models, Molecular, Molecular Structure, Neovascularization, Pathologic, Oligonucleotide Array Sequence Analysis, Protein Binding, Vascular Endothelial Growth Factor A, p300-CBP Transcription Factors
J. Am. Chem. Soc.
Date: Dec. 23, 2009
PubMed ID: 20000859
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