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

被引：74

作者：

Block, Katherine M. ^{[1
,2
]}

Wang, Hui ^{[1
]}

Szabo, Lajos Z. ^{[1
]}

Polaske, Nathan W. ^{[1
]}

Henchey, Laura K. ^{[4
]}

Dubey, Ramin ^{[1
]}

Kushal, Swati ^{[1
]}

Laszlo, Csaba F. ^{[1
]}

Makhoul, Joshua ^{[1
]}

Song, Zuohe ^{[3
]}

Meuillet, Emmanuelle J. ^{[3
,5
,6
]}

Olenyuk, Bogdan Z. ^{[1
,3
]}

机构：

[1] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA

[2] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA

[3] Arizona Canc Ctr, Tucson, AZ 85724 USA

[4] NYU, Dept Chem, New York, NY 10003 USA

[5] Univ Arizona, Dept Nutr Sci, Tucson, AZ 85721 USA

[6] Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2009年 / 131卷 / 50期

基金：

美国国家科学基金会;

关键词：

ENDOTHELIAL GROWTH-FACTOR; STRUCTURAL BASIS; GENE-EXPRESSION; KEY REGULATOR; CANCER; PROTEIN; ANGIOGENESIS; MECHANISM; TARGETS; SUPPRESSION;

D O I：

10.1021/ja807601b

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：18078 / 18088

页数：11

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