Novel Small-Molecule Inhibitors of the Vascular Endothelial Growth Factor Receptor

2007 ◽  
Vol 8 ◽  
pp. S74-S78 ◽  
Author(s):  
Alex A. Adjei
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction

2010 ◽  
Vol 53 (5) ◽  
pp. 2215-2226 ◽  
Author(s):  
Ashley Jarvis ◽  
Charles K. Allerston ◽  
Haiyan Jia ◽  
Birger Herzog ◽  
Acely Garza-Garcia ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Vascular Endothelial ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor

scholarly journals Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood–retinal barrier dysfunction

2012 ◽  
Vol 446 (3) ◽  
pp. 455-467 ◽  
Author(s):  
Paul M. Titchenell ◽  
Cheng-Mao Lin ◽  
Jason M. Keil ◽  
Jeffrey M. Sundstrom ◽  
Charles D. Smith ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Endothelial Permeability ◽  
Kinase Assay ◽  
Vascular Endothelial ◽  
Blood Retinal Barrier ◽  
Atypical Pkc ◽  
Endothelial Growth Factor

Pro-inflammatory cytokines and growth factors such as VEGF (vascular endothelial growth factor) contribute to the loss of the BRB (blood–retinal barrier) and subsequent macular oedema in various retinal pathologies. VEGF signalling requires PKCβ [conventional PKC (protein kinase C)] activity; however, PKCβ inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability, suggesting the involvement of alternative signalling pathways. In the present study, we provide evidence for the involvement of aPKC (atypical PKC) signalling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small-molecule inhibitors, and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small-molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. The results of the present study suggest that aPKC inhibition with 2-amino-4-phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis, and the BBB (blood–brain barrier) in the presence of brain tumours.

Fortgeschrittenes medulläres Schilddrüsenkarzinom: Vandetanib verbessert das progressionsfreie Überleben

2012 ◽  
Vol 03 (02) ◽  
pp. 93-92
Author(s):  
Alexander Kretzschmar
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Medulläres Schilddrüsenkarzinom ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Vandetanib ist ein oraler Hemmer des RET-Kinase-, VEGF (Vascular Endothelial Growth Factor Receptor)- und EGFR (Epidermal Growth Factor Receptor)-Signalwegs. In einer zulassungsrelevanten, randomisierten, doppelblinden, placebokontrollierten Phase- III-Studie verlängerte der Tyrosinkinasehemmer das progressionsfreie Überleben (PFS) signifikant länger als Placebo.

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