Download MendeleyN-(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.
Hennequin, L.F., Allen, J., Breed, J., Curwen, J., Fennell, M., Green, T.P., Lambert-van der Brempt, C., Morgentin, R., Norman, R.A., Olivier, A., Otterbein, L., Ple, P.A., Warin, N., Costello, G.(2006) J Med Chem 49: 6465-6488
- PubMed: 17064066
- DOI: https://doi.org/10.1021/jm060434q
- Primary Citation of Related Structures:
2H8H - PubMed Abstract:
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.
Organizational Affiliation:
Centre de Recherches, AstraZeneca, ZISE La Pompelle, B.P. 1050, 51689 Reims Cedex 2, France. [email protected]
