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Discovery of Potent Vascular Endothelial Growth Factor Receptor‐2 Inhibitors
Author(s) -
Papakyriakou Athanasios,
Katsarou Maria E.,
Belimezi Maria,
Karpusas Michael,
Vourloumis Dionisios
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900373
Subject(s) - angiogenesis , vascular endothelial growth factor , kinase insert domain receptor , docking (animal) , receptor tyrosine kinase , vegf receptors , chemistry , mediator , cancer research , tyrosine kinase , pharmacology , in vitro , vascular endothelial growth factor a , receptor , biology , microbiology and biotechnology , biochemistry , medicine , nursing
Substantial evidence over the last decades has implicated uncontrolled angiogenesis with various pathological states, including cancer. Vascular endothelial growth factor (VEGF) plays a critical role in its regulation. Because the tyrosine kinase VEGF receptor‐2 (VEGFR‐2) is the major mediator of the mitogenic, angiogenic, and permeability‐enhancing effects of VEGF, it has become one of the most profound anti‐angiogenesis targets. Inspired by the anthranilamide class of VEGFR‐2 inhibitors, we performed a computational analysis of some potent representative members, using docking and molecular dynamics calculations. Based on the observations drawn from introducing the effect of the receptor's flexibility in implicit aqueous environment, we designed, synthesized, and characterized several new analogues of related scaffolds with modifications in their steric and electronic characteristics. In vitro evaluation of these compounds revealed several novel VEGFR‐2 inhibitors that are less cytotoxic and more potent than the parent compounds.