Inhibition of hypoxia-inducible transcription factor complex with designed epipolythiodiketopiperazine

Designed small molecule inhibitors of hypoxia‐inducible gene expression have potential to become new research tools for molecular biology, genetics and serve as leads to new therapeutics. We report design, synthesis evaluation of biological activity, and a preliminary mechanistic study of epipolythi...

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Bibliographic Details
Published in:Biopolymers 2011-01, Vol.95 (1), p.8-16
Main Authors: Kushal, Swati, Wang, Hui, László, Csaba F., Szábo, Lajos Z., Olenyuk, Bogdan Z.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
angiogenesis
Biopolymers
Cell Line, Tumor
Cell Survival - drug effects
epipolythiodiketopiperazine
Gene expression
Gene Expression Regulation - drug effects
Genetics
Humans
hypoxia-inducible factor
Hypoxia-Inducible Factor 1 - antagonists & inhibitors
Inhibition
Inhibitors
Molecular biology
Molecular Sequence Data
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacology
Reproduction
Synthesis
transcription
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Summary:Designed small molecule inhibitors of hypoxia‐inducible gene expression have potential to become new research tools for molecular biology, genetics and serve as leads to new therapeutics. We report design, synthesis evaluation of biological activity, and a preliminary mechanistic study of epipolythiodiketopiperazine (ETP) transcriptional antagonist that targets the interaction between the C‐terminal transactivation domain (C‐TAD) of hypoxia‐inducible factor 1α (HIF‐1α) and cysteine‐histidine rich region (CH1) of transcriptional coactivator p300/CBP. Our results indicate that in cultured cells synthetic ETP 3 disrupts the structure and function of this complex in a dose‐dependent manner, resulting in rapid downregulation of hypoxia‐inducible gene expression. © 2010 Wiley Periodicals, Inc. Biopolymers 95: 8–16, 2011.
ISSN:0006-3525
1097-0282
1097-0282
DOI:10.1002/bip.21550