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

作者：Block Katherine M; Wang Hui; Szabo Lajos Z; Polaske Nathan W; Henchey Laura K; Dubey Ramin; Kushal Swati; Laszlo Csaba F; Makhoul Joshua; Song Zuohe; Meuillet Emmanuelle J; Olenyuk Bogdan Z^*

来源：Journal of the American Chemical Society, 2009, 131(50): 18078-18088.

DOI：10.1021/ja807601b

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-1 alpha. 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.

• 出版日期2009-12-23