Jarvis, A and Allerston, CK and Jia, HY and Herzog, B and Garza-Garcia, A and Winfield, N and Ellard, K and Aqil, R and Lynch, R and Chapman, C and Hartzoulakis, B and Nally, J and Stewart, M and Cheng, LL and Menon, M and Tickner, M and Djordjevic, S and Driscoll, PC and Zachary, I and Selwood, DL (2010) Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction. J MED CHEM , 53 (5) 2215 - 2226. 10.1021/jm901755g.
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We report the molecular design and synthesis of EG00229,2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis Studies localized VEGF-A binding in the NRP1 b1 domain and it peptide Fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells wits reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.
|Title:||Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction|
|Keywords:||ANTI-VEGF, SOFTWARE, BINDING, LIGAND, CELLS, MODEL|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Structural and Molecular Biology|
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Cardiovascular Medicine
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