Identification and characterization of small-molecule inhibitors of Tie2 kinase

Jinqi Liu, Tsung H. Lin, Andrew G. Cole, Rong Wen, Lian Zhao, Marc Raleigh Brescia, Biji Jacob, Zahid Hussain, Kenneth C. Appell, Ian Henderson, Maria L. Webb

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC50 value at 0.3 μM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders.

Original languageEnglish (US)
Pages (from-to)785-791
Number of pages7
JournalFEBS letters
Volume582
Issue number5
DOIs
StatePublished - Mar 5 2008
Externally publishedYes

Keywords

  • Angiogenesis
  • Choroidal neovascularization
  • CYP450, selectivity
  • Small-molecule inhibitor
  • Solubility
  • Stability
  • Tie2

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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