20150-84-9Relevant academic research and scientific papers
Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands
Inglis, Steven,Jones, Rhiannon,Fritz, Daniel,Stojkoski, Cvetan,Booker, Grant,Pyke, Simon
, p. 2543 - 2557 (2007/10/03)
The Src homology 3 (SH3) domains are small protein-protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines
Identification and specificity studies of small-molecule ligands for SH3 protein domains
Inglis, Steven R.,Stojkoski, Cvetan,Branson, Kim M.,Cawthray, Jacquie F.,Fritz, Daniel,Wiadrowski, Emma,Pyke, Simon M.,Booker, Grant W.
, p. 5405 - 5417 (2007/10/03)
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.
