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

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.