title: Targeting the proangiogenic VEGF-VEGFR protein-protein interface with drug-like compounds by in silico and in vitro screening.
abstract: Protein-protein interactions play a central role in medicine, and their modulation with small organic compounds remains an enormous challenge. Because it has been noted that the macromolecular complexes modulated to date have a relatively pronounced binding cavity at the interface, we decided to perform screening experiments over the vascular endothelial growth factor receptor (VEGFR), a validated target for antiangiogenic treatments with a very flat interface. We focused the study on the VEGFR-1 D2 domain, and 20 active compounds were identified. These small compounds contained a (3-carboxy-2-ureido)thiophen unit and had IC(50) values in the low micromolar range. The most potent compound inhibited the VEGF-induced VEGFR-1 transduction pathways. Our findings suggest that our best hit may be a promising scaffold to probe this macromolecular complex and for the development of treatments of VEGFR-1-dependent diseases.
authors.affiliation: Université Paris Descartes, CNRS UMR 8601, UFR biomédicale, 75006 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gautier
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.forename: Victor
authors.initials: V
authors.lastname: Goncalves
authors.forename: Florent
authors.initials: F
authors.lastname: Huguenot
authors.forename: Pascale
authors.initials: P
authors.lastname: Coric
authors.forename: Serge
authors.initials: S
authors.lastname: Bouaziz
authors.forename: Bili
authors.initials: B
authors.lastname: Seijo
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gaucher
authors.forename: Isabelle
authors.initials: I
authors.lastname: Broutin
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Aurelien
authors.initials: A
authors.lastname: Lesnard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: Nicolas
authors.initials: N
authors.lastname: Inguimbert
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D015195:Drug Design; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D054852:Small Molecule Libraries; D013876:Thiophenes; D042461:Vascular Endothelial Growth Factor A; C045141:thiophane; D040262:Receptors, Vascular Endothelial Growth Factor