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|Title:||Identification and specificity studies of small-molecule ligands for SH3 protein domains|
|Citation:||Journal of Medicinal Chemistry, 2004; 47(22):5405-5417|
|Publisher:||Amer Chemical Soc|
|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|
|Appears in Collections:||Molecular and Biomedical Science publications|
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