N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor
| Autor: | Allen Jack Mcqueen, Jason Breed, Tim P. Green, Patrick Ple, Nicolas Warin, Rémy Morgentin, Richard A. Norman, Michael Fennell, Gerard Costello, Christine Lambert-van der Brempt, Annie Olivier, Ludovic Otterbein, Jon Curwen, Laurent Francois Andre Hennequin |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Models Molecular Chemical Phenomena Stereochemistry Transplantation Heterologous Mice Nude Antineoplastic Agents Crystallography X-Ray Mice Structure-Activity Relationship Dogs In vivo Drug Discovery Transferase Animals Humans Neoplasm Invasiveness Benzodioxoles Enzyme Inhibitors Cell Proliferation ABL biology Chemistry Kinase Chemistry Physical 3T3 Cells Protein-Tyrosine Kinases Rats Transplantation src-Family Kinases Solubility Enzyme inhibitor biology.protein Quinazolines Molecular Medicine Thermodynamics Female Indicators and Reagents Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of medicinal chemistry. 49(22) |
| ISSN: | 0022-2623 |
| Popis: | Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man. |
| Databáze: | OpenAIRE |
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