title: A wrench-shaped synthetic molecule that modulates a transcription factor-coactivator interaction.
abstract: 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.
authors.affiliation: The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimogawa
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.forename: Qian
authors.initials: Q
authors.lastname: Mao
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kawazoe
authors.forename: Yongmun
authors.initials: Y
authors.lastname: Choi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Asada
authors.forename: Hideo
authors.initials: H
authors.lastname: Kigoshi
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D000218:Adamantane; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019793:Fluorescein / Q000737:chemistry; D018734:Genes, erbB-2 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles; D056892:Mediator Complex; D008958:Models, Molecular; D020005:Propanols / Q000737:chemistry* / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000218:Adamantane; D001952:Bridged-Ring Compounds; D004268:DNA-Binding Proteins; D019793:Fluorescein; D007211:Indoles; D056892:Mediator Complex; D020005:Propanols; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; C105529:ELF3 protein, human; C492159:MED23 protein, human; C474394:adamanolol; C486112:wrenchnolol