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Updated: Jun 17, 2026

Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine
Katherine M Block1, Hui Wang, Lajos Z Szabó
1Department of Chemistry and Biochemistry, The University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, USA.
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.
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