SAR131675

SAR131675 is an ATP-competitive inhibitor of VEGF receptor 3 (VEGFR3) with an IC₅₀ value of 23 nM for the human recombinant receptor in a cell-free assay.¹ It is selective for VEGFR3 over VEGFR2 and VEGFR1 (IC₅₀s = 230 and >3,000 nM, respectively). SAR131675 inhibits survival of human lymphatic cells cultured with the VEGFR3-specific ligands VEGF-C and VEGF-D over the non-specific ligand VEGF-A in vitro (IC₅₀s = 14, 17, and 664 nM, respectively). It decreases VEGF-C and VEGF-A-induced migration of human microvascular endothelial cells (HMVECs) when used at concentrations of 100 and 300 nM. SAR131675 (100 mg/kg) reduces tumor size, decreases the number of pancreatic angiogenic islets, and increases survival in the RIP1-Tag2 transgenic mouse model of pancreatic neuroendocrine tumors. It also decreases tumor size, levels of VEGFR3 in mammary tumor lysates, number of tumor-associated macrophages in mammary tumors, and the number of lung metastases in a 4T1 mouse allograft model when administered at a dose of 100 mg/kg.

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1. Alam, A., Blanc, I., Gueguen-Dorbes, G., et al. SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities. Mol. Cancer Ther. 11(8), 1637-1649 (2012).