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Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction
[Image: see text] 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 b...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841442/ https://www.ncbi.nlm.nih.gov/pubmed/20151671 http://dx.doi.org/10.1021/jm901755g |
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author | Jarvis, Ashley Allerston, Charles K. Jia, Haiyan Herzog, Birger Garza-Garcia, Acely Winfield, Natalie Ellard, Katie Aqil, Rehan Lynch, Rosemary Chapman, Chris Hartzoulakis, Basil Nally, James Stewart, Mark Cheng, Lili Menon, Malini Tickner, Michelle Djordjevic, Snezana Driscoll, Paul C. Zachary, Ian Selwood, David L. |
author_facet | Jarvis, Ashley Allerston, Charles K. Jia, Haiyan Herzog, Birger Garza-Garcia, Acely Winfield, Natalie Ellard, Katie Aqil, Rehan Lynch, Rosemary Chapman, Chris Hartzoulakis, Basil Nally, James Stewart, Mark Cheng, Lili Menon, Malini Tickner, Michelle Djordjevic, Snezana Driscoll, Paul C. Zachary, Ian Selwood, David L. |
author_sort | Jarvis, Ashley |
collection | PubMed |
description | [Image: see text] 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 a 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 was 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. |
format | Text |
id | pubmed-2841442 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-28414422010-03-18 Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction Jarvis, Ashley Allerston, Charles K. Jia, Haiyan Herzog, Birger Garza-Garcia, Acely Winfield, Natalie Ellard, Katie Aqil, Rehan Lynch, Rosemary Chapman, Chris Hartzoulakis, Basil Nally, James Stewart, Mark Cheng, Lili Menon, Malini Tickner, Michelle Djordjevic, Snezana Driscoll, Paul C. Zachary, Ian Selwood, David L. J Med Chem [Image: see text] 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 a 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 was 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. American Chemical Society 2010-02-12 2010-03-11 /pmc/articles/PMC2841442/ /pubmed/20151671 http://dx.doi.org/10.1021/jm901755g Text en Copyright © 2010 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
spellingShingle | Jarvis, Ashley Allerston, Charles K. Jia, Haiyan Herzog, Birger Garza-Garcia, Acely Winfield, Natalie Ellard, Katie Aqil, Rehan Lynch, Rosemary Chapman, Chris Hartzoulakis, Basil Nally, James Stewart, Mark Cheng, Lili Menon, Malini Tickner, Michelle Djordjevic, Snezana Driscoll, Paul C. Zachary, Ian Selwood, David L. Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction |
title | Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction |
title_full | Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction |
title_fullStr | Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction |
title_full_unstemmed | Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction |
title_short | Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction |
title_sort | small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor a (vegf-a) interaction |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841442/ https://www.ncbi.nlm.nih.gov/pubmed/20151671 http://dx.doi.org/10.1021/jm901755g |
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