Ruspharmtech LLC, Saint Petersburg, Russia.
Altogen Labs, Austin, TX, USA.
Eur J Cancer. 2016 Jul;61:20-8. doi: 10.1016/j.ejca.2016.03.068. Epub 2016 Apr 29.
Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers.
阿罗法尼布（RPT835）是一种新型的成纤维细胞生长因子受体 2（FGFR2）选择性别构抑制剂。我们之前的研究表明，阿罗法尼布可以与 FGFR2 的细胞外结构域结合，并对 FGF2 诱导的 FRS2α磷酸化具有抑制作用。在本研究中，我们进一步表明，阿罗法尼布可以抑制不同 FGFR2 同工型表达的癌细胞中 FRS2α的磷酸化，其半数最大抑制浓度（IC50）值为 7 和 9 nmol/L。在代表几种肿瘤类型（三阴性乳腺癌、黑色素瘤和卵巢癌）的四个细胞系中，阿罗法尼布抑制 FGF 介导的增殖，其 50%生长抑制（GI50）值为 16-370 nmol/L。与比伐芦单抗和贝伐珠单抗相比，阿罗法尼布可剂量依赖性地抑制人和小鼠内皮细胞的增殖和迁移（GI50 为 11-58 nmol/L）。阿罗法尼布治疗可消除体内实验性 FGF 诱导的血管生成。在 FGFR 驱动的人肿瘤异种移植模型中，阿罗法尼布的口服给药具有良好的耐受性，并表现出强大的抗肿瘤活性。重要的是，阿罗法尼布在 FGFR2 表达模型中有效。这些结果表明阿罗法尼布是一种有效的 FGFR2 抑制剂，为其在 FGFR2 驱动的癌症患者中的评估提供了强有力的依据。
