Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor

Mol Cancer Ther. 2006 Apr;5(4):995-1006. doi: 10.1158/1535-7163.MCT-05-0410.

Abstract

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cornea
  • Edema
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Indazoles / pharmacology*
  • Mice
  • Neovascularization, Physiologic / drug effects
  • Phenylurea Compounds / pharmacology*
  • Phosphorylation
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Retinal Vessels / drug effects
  • Retinal Vessels / physiology
  • Uterus / drug effects
  • Uterus / physiopathology

Substances

  • Enzyme Inhibitors
  • Indazoles
  • N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
  • Phenylurea Compounds
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor
  • Receptors, Vascular Endothelial Growth Factor