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.

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.

• Authors: Laurent F Hennequin, Jack Allen, Jason Breed, Jon Curwen, Michael Fennell, Tim P Green, Christine Lambert-van der Brempt, Rémy Morgentin, Richard A Norman, Annie Olivier, Ludovic Otterbein, Patrick A Plé, Nicolas Warin, Gerard Costello
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 22 Pg. 6465-88 (Nov 02 2006) ISSN: 0022-2623 [Print] United States
• PMID: 17064066 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzodioxoles
• Enzyme Inhibitors
• Indicators and Reagents
• Quinazolines
• saracatinib
• ARG tyrosine kinase
• Protein-Tyrosine Kinases
• src-Family Kinases

Topics

• 3T3 Cells
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Benzodioxoles (chemical synthesis, pharmacokinetics, pharmacology)
• Cell Proliferation (drug effects)
• Chemical Phenomena
• Chemistry, Physical
• Crystallography, X-Ray
• Dogs
• Enzyme Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Female
• Humans
• Indicators and Reagents
• Male
• Mice
• Mice, Nude
• Models, Molecular
• Neoplasm Invasiveness (prevention & control)
• Protein-Tyrosine Kinases (antagonists & inhibitors, chemistry)
• Quinazolines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Solubility
• Structure-Activity Relationship
• Thermodynamics
• Transplantation, Heterologous
• src-Family Kinases (antagonists & inhibitors, biosynthesis, chemistry)