A wrench-shaped synthetic molecule that modulates a transcription factor-coactivator interaction.

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.
Mesh Terms:
Adamantane, Biomimetic Materials, Bridged Compounds, Cell Line, Tumor, DNA-Binding Proteins, Fluorescein, Genes, erbB-2, Humans, Indoles, Mediator Complex, Models, Molecular, Propanols, Proto-Oncogene Proteins, Receptor, erbB-2, Structure-Activity Relationship, Trans-Activators, Transcription Factors, Transcriptional Activation
J. Am. Chem. Soc.
Date: Mar. 24, 2004
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