title: Targeting vascular endothelial growth factor receptor 2 and protein kinase D1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro.
abstract: Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways.
authors: Pathobiochemistry Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors: Attila
authors: A
authors: Varga
authors: Pathobiochemistry Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors: Pál
authors: P
authors: Gyulavári
authors: Vichem Chemie Research Ltd., Budapest, Hungary.
authors: Zoltán
authors: Z
authors: Greff
authors: Department of Physiology, Semmelweis University, Budapest, Hungary.
authors: Krisztina
authors: K
authors: Futosi
authors: Department of Physiology, Semmelweis University, Budapest, Hungary.
authors: Tamás
authors: T
authors: Németh
authors: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Laura
authors: L
authors: Simon-Szabó
authors: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Krisztina
authors: K
authors: Kerekes
authors: Vichem Chemie Research Ltd., Budapest, Hungary.
authors: Csaba
authors: C
authors: Szántai-Kis
authors: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors: Diána
authors: D
authors: Brauswetter
authors: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors: Márton
authors: M
authors: Kokas
authors: Pathobiochemistry Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors: Gábor
authors: G
authors: Borbély
authors: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Anna
authors: A
authors: Erdei
authors: Department of Physiology, Semmelweis University, Budapest, Hungary.
authors: Attila
authors: A
authors: Mócsai
authors: Pathobiochemistry Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary; Vichem Chemie Research Ltd., Budapest, Hungary; Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors: György
authors: G
authors: Kéri
authors: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors: Tibor
authors: T
authors: Vántus
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009389:Neovascularization, Pathologic; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011728:Pyridones / Q000737:chemistry / Q000633:toxicity*; D011743:Pyrimidines / Q000737:chemistry / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C000606722:VCC251801; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; C089212:protein kinase D; D040301:Vascular Endothelial Growth Factor Receptor-2; D011493:Protein Kinase C