A Wrench-Shaped Synthetic Molecule that Modulates a Transcription Factor-Coactivator Interaction

Hiroki Shimogawa, Youngjoo Kwon, Qian Mao, Yoshinori Kawazoe, Yongmun Choi, Shinichi Asada, Hideo Kigoshi, Motonari Uesugi

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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 α-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.

Original languageEnglish
Pages (from-to)3461-3471
Number of pages11
JournalJournal of the American Chemical Society
Issue number11
StatePublished - 22 Mar 2004


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