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Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction
Open accessAbstract
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.
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Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Cited by
Neuropilin-1 is a host factor for SARS-CoV-2 infection
Daly, J. L., Simonetti, B., Klein, K., Chen, K.-E., Williamson, M. K., Antón-Plágaro, C., Shoemark, D. K., Simón-Gracia, L., Bauer, M., Hollandi, R., et al. (2020) · Science · doi:10.1126/science.abd3072 · Cited by 1,251
Hamerlik, P., Lathia, J. D., Rasmussen, R., Wu, Q., Bartkova, J., Lee, M., Moudry, P., Bartek, J., Fischer, W., Lukas, J., et al. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20111424 · Cited by 406
Prud’homme, G. J., & Glinka, Y. (2012) · Oncotarget · doi:10.18632/oncotarget.626 · Cited by 275
Neuropilin 1: function and therapeutic potential in cancer
Chaudhary, B., Khaled, Y. S., Ammori, B. J., & Elkord, E. (2014) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-013-1500-0 · Cited by 233
Hota, P. K., & Buck, M. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1019-0 · Cited by 170
Metadata
- Authors
- Jarvis, A., Allerston, C. K., Jia, H., Herzog, B., Garza-Garcia, A., Winfield, N., Ellard, K., Aqil, R., Lynch, R., Chapman, C., Hartzoulakis, B., Nally, J., Stewart, M., Cheng, L., Menon, M., Tickner, M., Djordjevic, S., Driscoll, P. C., Zachary, I., & Selwood, D. L.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-02-12
- Volume
- 53
- Issue
- 5
- Pages
- 2215-2226
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2011841073
- Cited by
- 200
- References
- 1
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Jarvis, A., Allerston, C. K., Jia, H., Herzog, B., Garza-Garcia, A., Winfield, N., Ellard, K., Aqil, R., Lynch, R., Chapman, C., Hartzoulakis, B., Nally, J., Stewart, M., Cheng, L., Menon, M., Tickner, M., Djordjevic, S., Driscoll, P. C., Zachary, I., & Selwood, D. L. (2010). Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm901755g
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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