Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine.
Publication/Presentation Date
12-23-2009
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.
Volume
131
Issue
50
First Page
18078
Last Page
18088
ISSN
1520-5126
Published In/Presented At
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. (2009). Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. Journal of the American Chemical Society, 131(50), 18078–18088. https://doi.org/10.1021/ja807601b
Disciplines
Medicine and Health Sciences
PubMedID
20000859
Department(s)
Fellows and Residents
Document Type
Article