A Gene-Expression Inhibitor that Targets an α-Helix-Mediated Protein Interaction

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Abstract
Protein-protein interactions are harder to target by small organic molecules than by enzymes or nuclear hormone receptors. Here we report the discovery of an organic compound that inhibits the expression of the Her2 oncogene by disrupting an alpha-helix-mediated protein interaction. The druglike molecule we named adamanolol competitively inhibited the interaction between the two cancer-linked nuclear proteins, ESX (an epithelial-specific transcription factor) and Sur-2/DRIP130 (a Ras-linked subunit of the human mediator complex), which is important for the overexpression of Her2 gene in malignant breast cancer cells. Adamanolol impaired Her2 expression and caused cell death selectively in Her2-positive breast cancer cells. NMR signals of adamanolol suggest that its rigid conformation plays a role in forming a helixlike surface for the interaction.