Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema

J Cell Physiol. 2008 Jul;216(1):29-37. doi: 10.1002/jcp.21426.


Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema.

MeSH terms

  • Administration, Topical
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / metabolism
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Cell Line
  • Choroidal Neovascularization / drug therapy*
  • Choroidal Neovascularization / pathology
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Papilledema / drug therapy*
  • Papilledema / pathology
  • Phenols / therapeutic use*
  • Prodrugs / adverse effects
  • Prodrugs / metabolism
  • Prodrugs / therapeutic use*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / therapeutic use*
  • Rabbits
  • Rats
  • Rats, Long-Evans
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Retina / cytology
  • Retina / metabolism
  • Retina / pathology
  • Triazines / therapeutic use*
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism


  • 4-chloro-3-(5-methyl-3-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)-1,2,4-benzotriazin-7-yl)phenol
  • Angiogenesis Inhibitors
  • Phenols
  • Prodrugs
  • Protein Kinase Inhibitors
  • Triazines
  • Receptor Protein-Tyrosine Kinases
  • src-Family Kinases