Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model

Lucia Borriello; Matthieu Montès; Yves Lepelletier; Bertrand Leforban; Wang Qing Liu; Luc Demange; Brigitte Delhomme; Serena Pavoni; Rafika Jarray; Jean Luc Boucher; Sylvie Dufour; Olivier Hermine; Christiane Garbay; Réda Hadj-Slimane; Françoise Raynaud

doi:10.1016/j.canlet.2014.04.004

Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model

Lucia Borriello, Matthieu Montès, Yves Lepelletier, Bertrand Leforban, Wang Qing Liu, Luc Demange, Brigitte Delhomme, Serena Pavoni, Rafika Jarray, Jean Luc Boucher, Sylvie Dufour, Olivier Hermine, Christiane Garbay, Réda Hadj-Slimane, Françoise Raynaud

Cancer Signaling and Microenvironment (CSM)

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

46 Scopus citations

Abstract

Neuropilin-1/-2 (+33 NRPs), VEGF-A₁₆₅ co-receptors_, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A₁₆₅/NRPs protein-protein interaction antagonist (IC₅₀=34μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC₅₀=0.60μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67^low expression and apoptosis. Furthermore, CD31⁺/CD34⁺ vessels are reduced in accordance with HUVEC-tube formation inhibition (IC₅₀=0.20μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.

Original language	English
Pages (from-to)	120-127
Number of pages	8
Journal	Cancer Letters
Volume	349
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2014.04.004
State	Published - Jul 28 2014

Keywords

Animals
Antineoplastic Agents/chemistry
Apoptosis/drug effects
Breast Neoplasms/drug therapy
Cell Line, Tumor
Disease Progression
Drug Evaluation, Preclinical
Female
Human Umbilical Vein Endothelial Cells/drug effects
Humans
Ligands
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Models, Molecular
Molecular Docking Simulation
Neuropilins/antagonists & inhibitors
Peptide Fragments/antagonists & inhibitors
Small Molecule Libraries/chemistry
Structure-Activity Relationship
Vascular Endothelial Growth Factor A/antagonists & inhibitors
Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.canlet.2014.04.004

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Borriello, L., Montès, M., Lepelletier, Y., Leforban, B., Liu, W. Q., Demange, L., Delhomme, B., Pavoni, S., Jarray, R., Boucher, J. L., Dufour, S., Hermine, O., Garbay, C., Hadj-Slimane, R., & Raynaud, F. (2014). Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model. Cancer Letters, 349(2), 120-127. https://doi.org/10.1016/j.canlet.2014.04.004

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title = "Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model",

abstract = "Neuropilin-1/-2 (+33 NRPs), VEGF-A165 co-receptors, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A165/NRPs protein-protein interaction antagonist (IC50=34μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67low expression and apoptosis. Furthermore, CD31+/CD34+ vessels are reduced in accordance with HUVEC-tube formation inhibition (IC50=0.20μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.",

keywords = "Animals, Antineoplastic Agents/chemistry, Apoptosis/drug effects, Breast Neoplasms/drug therapy, Cell Line, Tumor, Disease Progression, Drug Evaluation, Preclinical, Female, Human Umbilical Vein Endothelial Cells/drug effects, Humans, Ligands, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Models, Molecular, Molecular Docking Simulation, Neuropilins/antagonists & inhibitors, Peptide Fragments/antagonists & inhibitors, Small Molecule Libraries/chemistry, Structure-Activity Relationship, Vascular Endothelial Growth Factor A/antagonists & inhibitors, Xenograft Model Antitumor Assays",

author = "Lucia Borriello and Matthieu Mont{\`e}s and Yves Lepelletier and Bertrand Leforban and Liu, {Wang Qing} and Luc Demange and Brigitte Delhomme and Serena Pavoni and Rafika Jarray and Boucher, {Jean Luc} and Sylvie Dufour and Olivier Hermine and Christiane Garbay and R{\'e}da Hadj-Slimane and Fran{\c c}oise Raynaud",

year = "2014",

month = jul,

day = "28",

doi = "10.1016/j.canlet.2014.04.004",

language = "English",

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journal = "Cancer Letters",

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Borriello, L, Montès, M, Lepelletier, Y, Leforban, B, Liu, WQ, Demange, L, Delhomme, B, Pavoni, S, Jarray, R, Boucher, JL, Dufour, S, Hermine, O, Garbay, C, Hadj-Slimane, R & Raynaud, F 2014, 'Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model', Cancer Letters, vol. 349, no. 2, pp. 120-127. https://doi.org/10.1016/j.canlet.2014.04.004

TY - JOUR

T1 - Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model

AU - Borriello, Lucia

AU - Montès, Matthieu

AU - Lepelletier, Yves

AU - Leforban, Bertrand

AU - Liu, Wang Qing

AU - Demange, Luc

AU - Delhomme, Brigitte

AU - Pavoni, Serena

AU - Jarray, Rafika

AU - Boucher, Jean Luc

AU - Dufour, Sylvie

AU - Hermine, Olivier

AU - Garbay, Christiane

AU - Hadj-Slimane, Réda

AU - Raynaud, Françoise

PY - 2014/7/28

Y1 - 2014/7/28

N2 - Neuropilin-1/-2 (+33 NRPs), VEGF-A165 co-receptors, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A165/NRPs protein-protein interaction antagonist (IC50=34μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67low expression and apoptosis. Furthermore, CD31+/CD34+ vessels are reduced in accordance with HUVEC-tube formation inhibition (IC50=0.20μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.

AB - Neuropilin-1/-2 (+33 NRPs), VEGF-A165 co-receptors, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A165/NRPs protein-protein interaction antagonist (IC50=34μM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60μM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67low expression and apoptosis. Furthermore, CD31+/CD34+ vessels are reduced in accordance with HUVEC-tube formation inhibition (IC50=0.20μM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.

KW - Animals

KW - Antineoplastic Agents/chemistry

KW - Apoptosis/drug effects

KW - Breast Neoplasms/drug therapy

KW - Cell Line, Tumor

KW - Disease Progression

KW - Drug Evaluation, Preclinical

KW - Female

KW - Human Umbilical Vein Endothelial Cells/drug effects

KW - Humans

KW - Ligands

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Mice, Transgenic

KW - Models, Molecular

KW - Molecular Docking Simulation

KW - Neuropilins/antagonists & inhibitors

KW - Peptide Fragments/antagonists & inhibitors

KW - Small Molecule Libraries/chemistry

KW - Structure-Activity Relationship

KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors

KW - Xenograft Model Antitumor Assays

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DO - 10.1016/j.canlet.2014.04.004

M3 - Article

C2 - 24752068

SN - 0304-3835

VL - 349

SP - 120

EP - 127

JO - Cancer Letters

JF - Cancer Letters

IS - 2

ER -

Structure-based discovery of a small non-peptidic Neuropilins antagonist exerting in vitro and in vivo anti-tumor activity on breast cancer model

Abstract

Keywords

UN SDGs

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