title: The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis.
abstract: EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein-protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.
authors.affiliation: Novartis Institutes for Biomedical Research, Expertise Platform Kinases, Novartis Campus, Fabrikstrasse 16, WJS152.1.72.2, 4056 Basel, Switzerland. georg.martiny-baron@novartis.com
authors.forename: Georg
authors.initials: G
authors.lastname: Martiny-Baron
authors.forename: Philipp
authors.initials: P
authors.lastname: Holzer
authors.forename: Eric
authors.initials: E
authors.lastname: Billy
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Joseph
authors.initials: J
authors.lastname: Brueggen
authors.forename: Mireille
authors.initials: M
authors.lastname: Ferretti
authors.forename: Niko
authors.initials: N
authors.lastname: Schmiedeberg
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Patricia
authors.initials: P
authors.lastname: Imbach
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001681:Biological Assay; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D012995:Solubility / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C558163:NVP BH6712; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A; D036224:Receptor, EphB4
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