Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/3058
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Type: Journal article
Title: Identification and specificity studies of small-molecule ligands for SH3 protein domains
Author: Inglis, S.
Stojkoski, C.
Branson, K.
Cawthray, J.
Fritz, D.
Wiadrowski, E.
Pyke, S.
Booker, G.
Citation: Journal of Medicinal Chemistry, 2004; 47(22):5405-5417
Publisher: Amer Chemical Soc
Issue Date: 2004
ISSN: 0022-2623
1520-4804
Statement of
Responsibility: 
Steven R. Inglis, Cvetan Stojkoski, Kim M. Branson, Jacquie F. Cawthray, Daniel Fritz, Emma Wiadrowski, Simon M. Pyke, and Grant W. Booker
Abstract: The Src Homology 3 (SH3) domains are small protein-protein interaction domains that bind proline-rich sequences and mediate a wide range of cell-signaling and other important biological processes. Since deregulated signaling pathways form the basis of many human diseases, the SH3 domains have been attractive targets for novel therapeutics. High-affinity ligands for SH3 domains have been designed; however, these have all been peptide-based and no examples of entirely nonpeptide SH3 ligands have previously been reported. Using the mouse Tec Kinase SH3 domain as a model system for structure-based ligand design, we have identified several simple heterocyclic compounds that selectively bind to the Tec SH3 domain. Using a combination of nuclear magnetic resonance chemical shift perturbation, structure-activity relationships, and site-directed mutagenesis, the binding of these compounds at the proline-rich peptide-binding site has been characterized. The most potent of these, 2-aminoquinoline, bound with Kd = 125 μM and was able to compete for binding with a proline-rich peptide. Synthesis of 6-substitued-2-aminoquinolines resulted in ligands with up to 6-fold improved affinity over 2-aminoquinoline and enhanced specificity for the Tec SH3 domain. Therefore, 2-aminoquinolines may potentially be useful for the development of high affinity small molecule ligands for SH3 domains.
Keywords: Animals; Mice; Quinazolines; Aminoquinolines; Proline; Ligands; Fluorescence Polarization; Magnetic Resonance Spectroscopy; Mutagenesis, Site-Directed; Sequence Alignment; Binding Sites; Binding, Competitive; Amino Acid Sequence; src Homology Domains; Structure-Activity Relationship; Models, Molecular; Molecular Sequence Data; Protein-Tyrosine Kinases
Description: © 2004 American Chemical Society
RMID: 0020041689
DOI: 10.1021/jm049533z
Published version: http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2004/47/i22/abs/jm049533z.html
Appears in Collections:Molecular and Biomedical Science publications
Chemistry publications

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