title: Discovery of potent vascular endothelial growth factor receptor-2 inhibitors.
abstract: 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.
authors.affiliation: Laboratory of Chemical Biology of Natural Products and Designed Molecules, Institute of Physical Chemistry, NCSR "Demokritos", 15310 Ag. Paraskevi Attikis, Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.forename: Maria E
authors.initials: ME
authors.lastname: Katsarou
authors.forename: Maria
authors.initials: M
authors.lastname: Belimezi
authors.forename: Michael
authors.initials: M
authors.lastname: Karpusas
authors.forename: Dionisios
authors.initials: D
authors.lastname: Vourloumis
mesh_terms: D002460:Cell Line; D030562:Databases, Protein; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D062367:ortho-Aminobenzoates; D040301:Vascular Endothelial Growth Factor Receptor-2; C000219:anthranilamide