Identification and characterization of small-molecule inhibitors of Tie2 kinase |
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Authors: | 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 |
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Institution: | Department of Biology, Pharmacopeia Inc, Cranbury, NJ 08512, USA. jliu@pcop.com |
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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 IC(50) value at 0.3 microM. 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. |
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Keywords: | Tie2 Small-molecule inhibitor Solubility Stability CYP450 selectivity Angiogenesis Choroidal neovascularization |
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