Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine

Katherine M. Block, Hui Wang, Lajos Z. Szabó, Nathan W. Polaske, Laura K. Henchey, Ramin Dubey, Swati Kushal, Csaba F. László, Joshua Makhoul, Zuohe Song, Emmanuelle J. Meuillet, Bogdan Z. Olenyuk

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


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-1R. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxiainducible genes critical for cancer progression. The observed effects are compound-specific and dosedependent. Controlling gene expression with designed small molecules targeting the transcription factorcoactivator interface may represent a new approach for arresting tumor growth.

Original languageEnglish (US)
Pages (from-to)18078-18088
Number of pages11
JournalJournal of the American Chemical Society
Issue number50
StatePublished - Dec 23 2009

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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