Direct Inhibition of Hypoxia-Inducible Transcription Factor Complex with Designed Dimeric Epidithiodiketopiperazine

Citations Over TimeTop 11% of 2009 papers

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.

Related Papers

• → Hypoxia Is Increasing in the Coastal Zone of the Baltic Sea(2011)511 cited
• → Hypoxia in Chesapeake Bay Tributaries: Worsening effects on Macrobenthic Community Structure in the York River(2009)31 cited
• → Upregulation of hypoxia-inducible factor (HIF)-1α and HIF-2α mRNA levels in dragonet Callionymus valenciennei exposed to environmental hypoxia in Tokyo Bay(2012)31 cited
• → SAT-179 A UNIQUE DISTRIBUTION OF HYPOXIA-INDUCIBLE FACTOR IN CULTURED TUBULAR CELLS IN HYPOPERFUSION MODEL(2020)
• → THE RESPONSE OF HYPOXIA BIOMARKERS TO HYPERBARIC OXYGEN THERAPY IN PREVENTING HYPOXIA AT HIGH ALTITUDE(2020)