m475271 and saracatinib

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.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Benzodioxoles; Cell Proliferation; Chemical Phenomena; Chemistry, Physical; Crystallography, X-Ray; Dogs; Enzyme Inhibitors; Female; Humans; Indicators and Reagents; Male; Mice; Mice, Nude; Models, Molecular; Neoplasm Invasiveness; Protein-Tyrosine Kinases; Quinazolines; Rats; Solubility; src-Family Kinases; Structure-Activity Relationship; Thermodynamics; Transplantation, Heterologous