SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic,anti-tumoral and anti-metastatic activities
Menée in vitro et in vivo, cette étude met en évidence des mécanismes d'action antitumorale et antimétastatique d'un composé appelé SAR131675, un inhibiteur sélectif de l'activité tyrosine kinase de VEGFR-3
SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase (TK) activity and VEGFR-3 autophosphorylation in HEK cells with IC50s of 20nM and 45nM, respectively. SAR131675 dose-dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC50 of about 20nM. SAR131675 was found to be highly selective for VEGFR-3 versus 107 receptors, enzymes, ion channels and 65 kinases. However, it exhibited a moderate activity on VEGFR-2 with a VEGFR-3/VEGFR-2 ratio of about 10. SAR131675 had no anti-proliferative activity on a panel of 30 tumors and primary cells, further demonstrating its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. SAR131675 was very well tolerated in mice and demonstrated a potent antitumoral effect in several orthotopic and syngenic models including mammary 4T1 carcinoma and the RIP1.Tag2 tumors. Interestingly, it significantly reduced lymph nodes invasion and lung metastasis demonstrating its anti-lymphangiogenic activity in vivo. Moreover, treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis. Tumor Associated Macrophages (TAMs) play an important role in tumor growth and metastasis. The expression of VEGFR-3 on TAMs has been recently described. F4/80 immunostaining clearly demonstrated that SAR131675 significantly reduced TAMs infiltration and aggregation in 4T1 tumors. Taken together, SAR131675 is the first highly specific VEGFR-3-TK inhibitor described to date, displaying significant anti-tumoral and anti-metastatic activities in vivo through inhibition of lymphangiogenesis and TAMs invasion.
http://mct.aacrjournals.org/content/early/2012/05/12/1535-7163.MCT-11-0866-T.abstract