Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity
Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity
复制标题
DOI：
10.1002/ijc.25864
复制
发表时间：
2011-07-01
影响因子：
6.4
通讯作者：
Zopf, Dieter
中科院分区：
文献类型：
--
作者：
Wilhelm, Scott M.;Dumas, Jacques;Zopf, Dieter
血管生成是肿瘤发展的关键驱动因素，由相互关联的信号通路控制。血管内皮生长因子受体（VEGFR）2和酪氨酸激酶与免疫球蛋白和表皮生长因子同源结构域2在正常和肿瘤血管的生物学中起着至关重要的作用。瑞戈非尼（BAY 73-4506）是一种新型口服多激酶抑制剂，在生化和细胞激酶磷酸化试验中有效抑制这些内皮细胞激酶。此外，瑞戈非尼还可抑制其他血管生成激酶（VEGFR 1/3、血小板衍生生长因子受体β和成纤维细胞生长因子受体1）以及突变型致癌激酶KIT、RET和B-RAF。通过动态对比增强磁共振成像在体内证明了瑞戈非尼的抗血管生成作用。以10 mg/kg剂量经口给予一次瑞戈非尼可显著降低大鼠GS 9 L胶质母细胞瘤异种移植物血管系统中Gadomer的外渗。在每日（qd）× 4给药研究中，药效学效应在末次给药后持续48小时，并与肿瘤生长抑制（TGI）相关。在10和30 mg/kg qdx 5给药后，在人结肠直肠异种移植物中观察到肿瘤微血管面积显著减少。在小鼠的各种临床前人异种移植模型中，瑞格非尼表现出强效的剂量依赖性TGI，在乳腺MDA-MB-231和肾786-O癌模型中观察到肿瘤收缩。乳腺模型的药效学分析显示，增殖标志物Ki-67和磷酸化细胞外调节激酶1/2的染色显著减少。这些数据表明，瑞戈非尼是一种耐受性良好的口服活性多激酶抑制剂，具有独特的靶向特征，可能对人类恶性肿瘤具有治疗益处。
Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-beta and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)x4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qdx5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.