title: SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities.
abstract: SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC(50) values of 20 and 45 nmol/L, respectively. SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC(50) of about 20 nmol/L. SAR131675 was found to be highly selective for VEGFR-3 versus 107 receptors, enzymes, ion channels, and 65 kinases. However, it was moderately active on VEGFR-2 with a VEGFR-3/VEGFR-2 ratio of about 10. SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells, further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models, including mammary 4T1 carcinoma and RIP1.Tag2 tumors. Interestingly, it significantly reduced lymph node invasion and lung metastasis, showing its antilymphangiogenic activity in vivo. Moreover, treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis. Tumor-associated macrophages (TAM) play an important role in tumor growth and metastasis. The expression of VEGFR-3 on TAMs has been recently described. F4/80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors. Taken together, SAR131675 is the first highly specific VEGFR-3-TK inhibitor described to date, displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion.
authors.affiliation: Sanofi Recherche et Développement, Early to Candidate DPU, 195, Route d'Espagne, 31036 Toulouse, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Alam
authors.forename: Isabelle
authors.initials: I
authors.lastname: Blanc
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gueguen-Dorbes
authors.forename: Olivier
authors.initials: O
authors.lastname: Duclos
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonnin
authors.forename: Pauline
authors.initials: P
authors.lastname: Barron
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Laplace
authors.forename: Gaelle
authors.initials: G
authors.lastname: Morin
authors.forename: Florence
authors.initials: F
authors.lastname: Gaujarengues
authors.forename: Frédérique
authors.initials: F
authors.lastname: Dol
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Hérault
authors.forename: Paul
authors.initials: P
authors.lastname: Schaeffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Savi
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C576806:SAR131675; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3