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Development of synthetic molecules that provide external control over the transcription of a given gene represents a challenge in medicinal and bioorganic chemistry. Here we report design and analysis of wrenchnolol, a wrench-shaped synthetic molecule that impairs the transcription of the Her2 oncogene by disrupting association of transcription factor ESX with its coactivator Sur-2. The "jaw" part of the compound mimics the alpha-helical interface of the activation domain of ESX, and the "handle" region accepts chemical modifications for a range of analysis. A water-soluble handle permitted NMR study in aqueous solution; a biotinylated handle verified the selectivity of the interaction, and a fluorescent handle confirmed the cell permeability of the compound. The case study of wrenchnolol foreshadows the promise and the challenge of targeting protein-protein interactions in the nucleus and may lead to the development of unique synthetic modulators of gene transcription.


Hiroki Shimogawa, Youngjoo Kwon, Qian Mao, Yoshinori Kawazoe, Yongmun Choi, Shinichi Asada, Hideo Kigoshi, Motonari Uesugi. A wrench-shaped synthetic molecule that modulates a transcription factor-coactivator interaction. Journal of the American Chemical Society. 2004 Mar 24;126(11):3461-71

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PMID: 15025473

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