Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/3058
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
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 |
DOI: | 10.1021/jm049533z |
Published version: | http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2004/47/i22/abs/jm049533z.html |
Appears in Collections: | Aurora harvest 6 Chemistry publications Molecular and Biomedical Science publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.