Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src
| Autor: | Patrick Ple, Gerard Costello, Tim P. Green, Michael Fennell, Allen Jack Mcqueen, Christine Lambert-van der Brempt, Laurent Francois Andre Hennequin, Jon Curwen |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Antineoplastic Agents Dioxoles Receptor tyrosine kinase CSK Tyrosine-Protein Kinase Mice Rats Nude Structure-Activity Relationship In vivo Drug Discovery Animals Neoplasm Invasiveness Phosphorylation Aniline Compounds biology Chemistry Kinase insert domain receptor 3T3 Cells Protein-Tyrosine Kinases Xenograft Model Antitumor Assays Rats src-Family Kinases Biochemistry Enzyme inhibitor biology.protein Quinazolines Molecular Medicine Tyrosine Signal transduction Tyrosine kinase Platelet-derived growth factor receptor Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of medicinal chemistry. 47(4) |
| ISSN: | 0022-2623 |
| Popis: | Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis. |
| Databáze: | OpenAIRE |
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