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Direct Inhibition of Hypoxia-Inducible Transcription Factor Complex with Designed Dimeric Epidithiodiketopiperazine
Open accessAbstract
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.
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Metadata
- Authors
- Block, K. M., Wang, H., Szabó, L. Z., Polaske, N. W., Henchey, L. K., Dubey, R., Kushal, S., László, C. F., Makhoul, J., Song, Z., Meuillet, E. J., & Olenyuk, B. Z.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Olenyuk, Bogdan Z.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-06-17
- Volume
- 131
- Issue
- 50
- Pages
- 18078-18088
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC2796602
- OpenAlex
- W2018666390
- Cited by
- 79
- References
- 47
- Citations by year
- 2024: 4 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 7 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 8 · 2013: 10 · 2012: 5
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01 CA96812, R01CA096812, R21CA129388)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- hypoxia-inducible factor-1α, HIF-1α, epidithiodiketopiperazines, hypoxia-inducible gene expression, tumor angiogenesis, metastasis, cancer energy metabolism, small molecule design
- MeSH terms
- Binding, Competitive, Cell Survival, Disulfides, Dose-Response Relationship, Drug, Humans, Luciferases, Models, Molecular, Neovascularization, Pathologic, Protein Binding, Molecular Structure, Cell Hypoxia, Gene Expression, Oligonucleotide Array Sequence Analysis, Angiogenesis Inhibitors, Gene Expression Profiling, Vascular Endothelial Growth Factor A, Cell Line, Tumor, p300-CBP Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, Diketopiperazines
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