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

• Published in: Journal of the American Chemical Society Vol. 126; no. 11; pp. 3461 - 3471
• Main Authors: Shimogawa, Hiroki, Kwon, Youngjoo, Mao, Qian, Kawazoe, Yoshinori, Choi, Yongmun, Asada, Shinichi, Kigoshi, Hideo, Uesugi, Motonari
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.03.2004; Amer Chemical Soc
• Subjects: Adamantane; Biological and medical sciences; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Cell Line, Tumor; Chemistry; Chemistry, Multidisciplinary; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fluorescein - chemistry; General pharmacology; Genes, erbB-2 - drug effects; Genes, erbB-2 - genetics; Humans; Indoles; Mediator Complex; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Physical Sciences; Physicochemical properties. Structure-activity relationships; Propanols - chemistry; Propanols - pharmacology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - genetics; Science & Technology; Structure-Activity Relationship; Trans-Activators; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - drug effects; ACTIVATION; COMPLEX; ALPHA-HELIX; HUMAN-BREAST-CANCER; PROTEIN ASSOCIATION; RECOGNITION; STRUCTURAL BASIS; GENE-EXPRESSION; INHIBITORS; RAS-CAAX; Antineoplastic agent; Antibiotic; Chemical modification; Structure activity relation; Molecular interaction; Chemical inhibition; NMR spectrometry; Transcription factor; Biological activity; Fluorescence spectrometry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja038855+

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.