Identification and characterization of small-molecule inhibitors of Tie2 kinase.
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.
Liu
Jinqi
J
Department of Biology, Pharmacopeia Inc, Cranbury, NJ 08512, USA. jliu@pcop.com
Lin
Tsung H
TH
Cole
Andrew G
AG
Wen
Rong
R
Zhao
Lian
L
Brescia
Marc-Raleigh
MR
Jacob
Biji
B
Hussain
Zahid
Z
Appell
Kenneth C
KC
Henderson
Ian
I
Webb
Maria L
ML
D042683:Angiopoietin-1 / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002829:Choroid / Q000098:blood supply / Q000473:pathology; D020256:Choroidal Neovascularization / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects
D042683:Angiopoietin-1; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D042787:Receptor, TIE-2