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Identification and characterization of small‐molecule inhibitors of Tie2 kinase
Author(s) -
Liu Jinqi,
Lin Tsung H.,
Cole Andrew G.,
Wen Rong,
Zhao Lian,
Brescia Marc-Raleigh,
Jacob Biji,
Hussain Zahid,
Appell Kenneth C.,
Henderson Ian,
Webb Maria L.
Publication year - 2008
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2008.02.003
Subject(s) - angiopoietin receptor , angiogenesis , chemistry , small molecule , kinase insert domain receptor , endothelial stem cell , receptor , matrigel , receptor protein tyrosine kinases , receptor tyrosine kinase , biochemistry , microbiology and biotechnology , pharmacology , biology , vascular endothelial growth factor a , cancer research , vascular endothelial growth factor , in vitro , vegf receptors
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 IC 50 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.