NRPa-308, a new neuropilin-1 antagonist, exerts in vitro anti-angiogenic and anti-proliferative effects and in vivo anti-cancer effects in a mouse xenograft model.
Cancer Lett
; 414: 88-98, 2018 02 01.
Article
en En
| MEDLINE
| ID: mdl-29111348
ABSTRACT
Neuropilin-1 (NRP-1) is an extra-cellular receptor for the main Vascular Endothelial Growth Factor over-expressed in tumour tissues, VEGF-A165. Consequently, NRP-1 is involved in angiogenesis and in tumour growth, and its over-expression is related to a clinical poor prognosis. NRP-1 appears as a major target in oncology, which remains poorly exploited. Herein, we report a new series of 18 small-sized fully organic VEGF-A165/NRP-1 antagonists (NRPas). These compounds share an original scaffold, including two linkers (sulphonamide and amide) and three aromatic cores. Among them, 2a (renamed NRPa-308) emerges as a promising "hit". In vitro,2a exerts not only potent anti-angiogenic activity, but also significant effects on cell viability of large panel of human solid and haematological cancer cell lines. Importantly, 2a is less cytotoxic on healthy tissues than the marketed anti-angiogenic drug sunitinib. Lastly, in a mouse xenograft model (human MDA-MB-231 breast cancer cells), 2a improves the median survival and reduces the tumour growth, but does not exert visible acute toxicity. Altogether, these results highlight its huge potential for a further "hit-to-lead" optimization, leading to new anti-cancer drugs.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores de la Angiogénesis
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Ensayos Antitumor por Modelo de Xenoinjerto
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Neuropilina-1
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Proliferación Celular
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Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Lett
Año:
2018
Tipo del documento:
Article
País de afiliación:
Francia