Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction

Ashley Jarvis; Charles K. Allerston; Haiyan Jia; Birger Herzog; Acely Garza-Garcia; Natalie Winfield; Katie Ellard; Rehan Aqil; Rosemary Lynch; Chris Chapman; Basil Hartzoulakis; James Nally; Mark Stewart; Lili Cheng; Malini Menon; Michelle Tickner; Snezana Djordjevic; Paul C. Driscoll; Ian Zachary; David L. Selwood

doi:10.1021/jm901755g

Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction

Ashley Jarvis, Charles K. Allerston, Haiyan Jia, Birger Herzog, Acely Garza-Garcia, Natalie Winfield, Katie Ellard, Rehan Aqil, Rosemary Lynch, Chris Chapman, Basil Hartzoulakis, James Nally, Mark Stewart, Lili Cheng, Malini Menon, Michelle Tickner, Snezana Djordjevic, Paul C. Driscoll, Ian Zachary, David L. Selwood

Research output: Contribution to journal › Article › peer-review

Abstract

We report the molecular design and synthesis of EG00229,2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRPl) and the structural characterization of NRPl-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRPl bl 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 NRPl 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.

Original language	English
Pages (from-to)	2215-2226
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	5
DOIs	https://doi.org/10.1021/jm901755g
Publication status	Published - 11 Mar 2010

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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, 53(5), 2215-2226. https://doi.org/10.1021/jm901755g

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title = "Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction",

abstract = "We report the molecular design and synthesis of EG00229,2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRPl) and the structural characterization of NRPl-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRPl bl 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 NRPl 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.",

author = "Ashley Jarvis and Allerston, {Charles K.} and Haiyan Jia and Birger Herzog and Acely Garza-Garcia and Natalie Winfield and Katie Ellard and Rehan Aqil and Rosemary Lynch and Chris Chapman and Basil Hartzoulakis and James Nally and Mark Stewart and Lili Cheng and Malini Menon and Michelle Tickner and Snezana Djordjevic and Driscoll, {Paul C.} and Ian Zachary and Selwood, {David L.}",

year = "2010",

month = mar,

day = "11",

doi = "10.1021/jm901755g",

language = "English",

volume = "53",

pages = "2215--2226",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society (ACS)",

number = "5",

}

Jarvis, A, Allerston, CK, 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, PC, Zachary, I & Selwood, DL 2010, 'Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction', Journal of Medicinal Chemistry, vol. 53, no. 5, pp. 2215-2226. https://doi.org/10.1021/jm901755g

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T1 - Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction

AU - Jarvis, Ashley

AU - Allerston, Charles K.

AU - Jia, Haiyan

AU - Herzog, Birger

AU - Garza-Garcia, Acely

AU - Winfield, Natalie

AU - Ellard, Katie

AU - Aqil, Rehan

AU - Lynch, Rosemary

AU - Chapman, Chris

AU - Hartzoulakis, Basil

AU - Nally, James

AU - Stewart, Mark

AU - Cheng, Lili

AU - Menon, Malini

AU - Tickner, Michelle

AU - Djordjevic, Snezana

AU - Driscoll, Paul C.

AU - Zachary, Ian

AU - Selwood, David L.

PY - 2010/3/11

Y1 - 2010/3/11

N2 - We report the molecular design and synthesis of EG00229,2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRPl) and the structural characterization of NRPl-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRPl bl 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 NRPl 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.

AB - We report the molecular design and synthesis of EG00229,2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRPl) and the structural characterization of NRPl-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRPl bl 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 NRPl 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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EP - 2226

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction

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