Design synthesis and preliminary biological activities of VEGF receptor antagonists. Victor Goncalves, Benoit Gautier, Christine Lenoir, Florent Huguenot, Christiane Garbay, Michel Vidal et Nicolas Inguimbert*. INSERM U648, Université Paris Descartes, Laboratoire de Pharmacochimie Moléculaire et Cellulaire 45 rue des Saints Pères, 75270 Paris.

Targeted therapies are emerging fields in the treatment of pathologies such as cancer as they represent considerable advantage being less toxic than traditional anti cancer drugs (targeting DNA or cell division) which are mostly characterized by severe adverse events. Indeed targeted therapies address directly the tumor cells while sparing damage to the surrounding healthy tissues. The anti-neoangiogenic approaches appear to be one of the most promising targeted therapies. Neo-angiogenesis is defined as new blood vessel formation starting from pre-existing endothelial structures and is implicated in various pathological phenomena such as cancer (Carmeliet et al 2005). Indeed, neo-angiogenesis is interlocked with cancer because these new blood vessels enable the supply of the nutrients and oxygen necessary for tumor growth. Consequently, inhibition of blood vessels sprouting in order to starve the tumor constitutes a new attractive anti-tumoral therapy (Folkman et al 1971). Several successful investigations have lead to clinical trials and proved that the blocking of tumor-angiogenesis leads to decrease of tumor size as well as to a slow down of the metastatic process. The most evident target in this neo-angiogenesis phenomenon is constituted by proteins of the vascular endothelial growth factor (VEGF) family and their receptors (VEGFR). In particular VEGFRs are drugable that means that drugs interacting with the receptor can reverse the disease progression (Ellis et al 2008). Furthermore VEGFRs are well accessible for therapeutics due to their location at the cell surface. Therefore we engaged some years ago in a research program centered on the development of antagonists (Benedetti et al 2006) preventing the binding of VEGF to the VEGF receptor 1. The available 3D structures of VEGF complexed with a domain of the VEGFR-1 (Wiesmann et al 1997), has allowed us to identify, synthesize and evaluate minimal active VEGF mimics (Goncalves et al 2007). Furthermore, the cyclic designed peptides has validated the VEGFR-1 epitope which was prone to a virtual ligand screening which has permit to identified heterocyclic (non-peptidic) antagonists which act also as VEGF mimics. In this contribution, the design, optimization of the antagonist as well as the preliminary biological data will be presented. Références. P. Carmeliet, 2005. Angiogenesis in life disease and medicine. Nature 438: 932-936. L.D. D'Andrea, A. Del Gatto, C. Pedone, E. Benedetti. 2006. Peptide-based molecules in angiogenesis. Chem Biol Drug Des. 67(2):115-126. L.M. Ellis, D. J. Hicklin. 2008. VEGF-targeted therapy: Mechanism of anti-tumour activity. Nature Rev. Cancer 8: 579-591. J. Folkman, 1971. Tumor angiogenesis: therapeutic implications. N. Eng. J. Med 285(21):1182-1186. V. Goncalves, B. Gautier, P. Coric, S. Bouaziz, C. Lenoir, C. Garbay, M. vidal, N. Inguimbert. 2007 Rational design, structure, and biological evaluation of cyclic peptides mimicking the vascular endothelial growth factor. J. Med. Chem. 50(21):5135-46. C. Wiesmann, G. Fuh, HW. Christinger, C. Eigenbrot, J.A. Wells, A.M. de Vos. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91(5):695-704. *Correspondance : [email protected]