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

J Med Chem. 2006 Nov 2;49(22):6465-88. doi: 10.1021/jm060434q.

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.

MeSH terms

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

Substances

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

Associated data

  • PDB/2H8H