title: A gene-expression inhibitor that targets an alpha-helix-mediated protein interaction.
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.
authors.affiliation: The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Asada
authors.forename: Yongmun
authors.initials: Y
authors.lastname: Choi
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D000218:Adamantane; D001667:Binding, Competitive; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D018734:Genes, erbB-2 / Q000187:drug effects / Q000235:genetics; D007211:Indoles; D056892:Mediator Complex; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000378:metabolism; D020005:Propanols / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D001952:Bridged-Ring Compounds; D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D007211:Indoles; C492159:MED23 protein, human; D056892:Mediator Complex; D010446:Peptide Fragments; D020005:Propanols; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D014157:Transcription Factors; C474394:adamanolol; D016650:Fluorescein-5-isothiocyanate; D000218:Adamantane