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. 2018 Feb 1:414:88-98. doi: 10.1016/j.canlet.2017.10.039.
Wang-Qing Liu  1 ,  Yves Lepelletier  2 ,  Matthieu Montès  3 ,  Lucia Borriello  4 ,  Rafika Jarray  5 ,  Renaud Grépin  6 ,  Bertrand Leforban  7 ,  Ali Loukaci  4 ,  Rachid Benhida  8 ,  Olivier Hermine  9 ,  Sylvie Dufour  10 ,  Gilles Pagès  11 ,  Christiane Garbay  12 ,  Françoise Raynaud  12 ,  Reda Hadj-Slimane  13 ,  Luc Demange  14
Affiliations
  • 1. INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France.
  • 2. INSERM UMR 1163, Laboratory of cellular and Molecular basis of normal hematopoiesis and hematological disorders, 24 boulevard Montparnasse, 75015, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris Cité, 24 boulevard Montparnasse, 75015, Paris, France; CNRS ERL 8254, 24 boulevard Montparnasse, 75015, Paris, France. Electronic address: [email protected].
  • 3. Conservatoire National des Arts et Métiers, Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, 292 rue Saint Martin, 75003 Paris, France.
  • 4. INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Tragex Pharma, 29 Rue Marcel Dassault, 92100, Boulogne-Billancourt, France.
  • 5. Sup'Biotech, 66 Rue Guy Môquet, 94800, Villejuif, France; CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Division of Prions and Related Diseases (SEPIA), 92260, Fontenay-aux- Roses, France.
  • 6. Centre Scientifique de Monaco, Biomedical Department, 8 Quai Antoine Ier, MC-98000, Monaco.
  • 7. INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Tragex Pharma, 29 Rue Marcel Dassault, 92100, Boulogne-Billancourt, France.
  • 8. Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108, Nice, France; Mohamed VI Polytechnic University, UM6P, 43150 Ben Guerir, Morocco.
  • 9. INSERM UMR 1163, Laboratory of cellular and Molecular basis of normal hematopoiesis and hematological disorders, 24 boulevard Montparnasse, 75015, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris Cité, 24 boulevard Montparnasse, 75015, Paris, France; CNRS ERL 8254, 24 boulevard Montparnasse, 75015, Paris, France.
  • 10. INSERM U955 UPEC, 51 Avenue du Maréchal Delattre de Tassigny, 94000, Créteil, France.
  • 11. Université Côte d'Azur, CNRS UMR 7284 and INSERM U 1081, Institute for Research on Cancer and Aging (IRCAN), 28 Avenue de Valombrose, 06107 Nice, France.
  • 12. INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France.
  • 13. Tragex Pharma, 29 Rue Marcel Dassault, 92100, Boulogne-Billancourt, France.
  • 14. INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108, Nice, France. Electronic address: [email protected].
PMID: 29111348 DOI: 10.1016/j.canlet.2017.10.039
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.

Keywords
Anti-angiogenic compound; In vivo tumour growth inhibition; Neuropilin antagonists; Tumour cell viability reduction.
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