SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC50 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 IC50 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. Mol Cancer Ther; 11(8); 1637–49. ©2012 AACR.

中文翻译：

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SAR131675，一种具有抗淋巴管生成、抗肿瘤和抗转移活性的强效选择性 VEGFR-3-TK 抑制剂

SAR131675 是一种有效的选择性 VEGFR-3 抑制剂。它抑制 HEK 细胞中 VEGFR-3 酪氨酸激酶活性和 VEGFR-3 自磷酸化，IC5​​0 值分别为 20 和 45 nmol/L。SAR131675 剂量依赖性地抑制由 VEGFR-3 配体 VEGFC 和 VEGFD 诱导的原代人类淋巴细胞的增殖，IC50 约为 20 nmol/L。与 107 种受体、酶、离子通道和 65 种激酶相比，SAR131675 对 VEGFR-3 具有高度选择性。然而，它对 VEGFR-2 具有中等活性，VEGFR-3/VEGFR-2 比率约为 10。SAR131675 对一组 30 个肿瘤和原代细胞没有抗增殖活性，进一步显示其高特异性并表明 SAR131675细胞毒剂或细胞抑制剂。SAR131675 在小鼠中具有很好的耐受性，并在多种原位和同基因模型中显示出有效的抗肿瘤作用，包括乳腺 4T1 癌和 RIP1.Tag2 肿瘤。有趣的是，它显着减少了淋巴结侵袭和肺转移，显示了其在体内的抗淋巴管生成活性。此外，在切除 4T1 原发肿瘤之前对小鼠进行治疗足以防止转移。肿瘤相关巨噬细胞 (TAM) 在肿瘤生长和转移中发挥重要作用。最近已经描述了 VEGFR-3 在 TAM 上的表达。F4/80 免疫染色清楚地表明 SAR131675 显着减少了 4T1 肿瘤中的 TAM 浸润和聚集。总之，SAR131675 是迄今为止描述的第一种高度特异性的 VEGFR-3-TK 抑制剂，通过抑制淋巴管生成和 TAM 侵袭，在体内显示出显着的抗肿瘤和抗转移活性。摩尔癌症治疗; 11(8); 1637-49 年。©2012 AACR。