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https://hdl.handle.net/2440/3058
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dc.contributor.author | Inglis, S. | - |
dc.contributor.author | Stojkoski, C. | - |
dc.contributor.author | Branson, K. | - |
dc.contributor.author | Cawthray, J. | - |
dc.contributor.author | Fritz, D. | - |
dc.contributor.author | Wiadrowski, E. | - |
dc.contributor.author | Pyke, S. | - |
dc.contributor.author | Booker, G. | - |
dc.date.issued | 2004 | - |
dc.identifier.citation | Journal of Medicinal Chemistry, 2004; 47(22):5405-5417 | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.issn | 1520-4804 | - |
dc.identifier.uri | http://hdl.handle.net/2440/3058 | - |
dc.description | © 2004 American Chemical Society | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Steven R. Inglis, Cvetan Stojkoski, Kim M. Branson, Jacquie F. Cawthray, Daniel Fritz, Emma Wiadrowski, Simon M. Pyke, and Grant W. Booker | - |
dc.language.iso | en | - |
dc.publisher | Amer Chemical Soc | - |
dc.source.uri | http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2004/47/i22/abs/jm049533z.html | - |
dc.subject | Animals | - |
dc.subject | Mice | - |
dc.subject | Quinazolines | - |
dc.subject | Aminoquinolines | - |
dc.subject | Proline | - |
dc.subject | Ligands | - |
dc.subject | Fluorescence Polarization | - |
dc.subject | Magnetic Resonance Spectroscopy | - |
dc.subject | Mutagenesis, Site-Directed | - |
dc.subject | Sequence Alignment | - |
dc.subject | Binding Sites | - |
dc.subject | Binding, Competitive | - |
dc.subject | Amino Acid Sequence | - |
dc.subject | src Homology Domains | - |
dc.subject | Structure-Activity Relationship | - |
dc.subject | Models, Molecular | - |
dc.subject | Molecular Sequence Data | - |
dc.subject | Protein-Tyrosine Kinases | - |
dc.title | Identification and specificity studies of small-molecule ligands for SH3 protein domains | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1021/jm049533z | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Pyke, S. [0000-0002-0061-5115] | - |
dc.identifier.orcid | Booker, G. [0000-0001-7207-4699] | - |
Appears in Collections: | Aurora harvest 6 Chemistry publications Molecular and Biomedical Science publications |
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