A Wrench-Shaped Synthetic Molecule that Modulates a Transcription Factor-Coactivator Interaction
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- 作者：Hiroki Shimogawa ; Youngjoo Kwon ; Qian Mao ; Yoshinori Kawazoe ; Yongmun Choi ; Shinichi Asada ; Hideo Kigoshi ; and Motonari Uesugi
- 刊名：Journal of the American Chemical Society
- 出版年：2004
- 出版时间：March 24, 2004
- 年：2004
- 卷：126
- 期：11
- 页码：3461 - 3471
- 全文大小：356K
- 年卷期：v.126,no.11(March 24, 2004)
- ISSN：1520-5126
文摘
Development of synthetic molecules that provide external control over the transcription of a givengene represents a challenge in medicinal and bioorganic chemistry. Here we report design and analysis ofwrenchnolol, a wrench-shaped synthetic molecule that impairs the transcription of the Her2 oncogene bydisrupting association of transcription factor ESX with its coactivator Sur-2. The "jaw" part of the compoundmimics the 
-helical interface of the activation domain of ESX, and the "handle" region accepts chemicalmodifications for a range of analysis. A water-soluble handle permitted NMR study in aqueous solution; abiotinylated handle verified the selectivity of the interaction, and a fluorescent handle confirmed the cellpermeability of the compound. The case study of wrenchnolol foreshadows the promise and the challengeof targeting protein-protein interactions in the nucleus and may lead to the development of unique syntheticmodulators of gene transcription.
-helical interface of the activation domain of ESX, and the "handle" region accepts chemicalmodifications for a range of analysis. A water-soluble handle permitted NMR study in aqueous solution; abiotinylated handle verified the selectivity of the interaction, and a fluorescent handle confirmed the cellpermeability of the compound. The case study of wrenchnolol foreshadows the promise and the challengeof targeting protein-protein interactions in the nucleus and may lead to the development of unique syntheticmodulators of gene transcription.