EMD 1214063 and EMD 1204831 Constitute a New Class of Potent and Highly Selective c-Met Inhibitors
EMD 1214063 and EMD 1204831 Constitute a New Class of Potent and Highly Selective c-Met Inhibitors
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DOI：
10.1158/1078-0432.ccr-12-3247
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发表时间：
2013-06-01
影响因子：
11.5
通讯作者：
Blaukat, Andree
中科院分区：
文献类型：
--
作者：
Bladt, Friedhelm;Faden, Bettina;Blaukat, Andree
目的：间充质-上皮转化因子（c-Met）受体，也称为肝细胞生长因子受体（HGFR），控制形态发生，这是胚胎发育和组织修复所需的生理过程。异常c-Met激活与多种人类恶性肿瘤相关，包括肺癌、肾癌、胃癌、肝癌和脑癌。在这项研究中，我们研究了两种新型化合物的特性，这些化合物在抗肿瘤治疗干预中选择性地抑制c-Met受体。实验设计：使用人癌细胞系和小鼠异种移植模型，在体外和体内研究了EMD 1214063和EMD 1204831的药理学特性、c-Met抑制活性和抗肿瘤作用。结果：EMD 1214063和EMD 1204831选择性抑制c-Met受体酪氨酸激酶活性。与它们对一组242种人激酶的作用相比，它们的抑制活性是强效的[抑制50%浓度（IC 50），分别为3 nmol/L和9 nmol/L]和高度选择性的。EMD 1214063和EMD 1204831均以剂量依赖性方式抑制c-Met磷酸化和下游信号传导，但其抑制活性的持续时间不同。在小鼠异种移植模型中，两种化合物均诱导人肿瘤消退，无论c-Met激活是否为HGF依赖性或独立性。这两种药物的耐受性良好，并诱导超过3周的treatment.Conclusions后没有实质性的体重减轻：我们的研究结果表明，选择性c-Met抑制EMD 1214063和EMD 1204831，并强烈支持这些化合物的分子靶向抗癌策略的背景下，临床试验。(c)2013年AACR。
Purpose: The mesenchymal-epithelial transition factor (c-Met) receptor, also known as hepatocyte growth factor receptor (HGFR), controls morphogenesis, a process that is physiologically required for embryonic development and tissue repair. Aberrant c-Met activation is associated with a variety of human malignancies including cancers of the lung, kidney, stomach, liver, and brain. In this study, we investigated the properties of two novel compounds developed to selectively inhibit the c-Met receptor in antitumor therapeutic interventions.Experimental Design: The pharmacologic properties, c-Met inhibitory activity, and antitumor effects of EMD 1214063 and EMD 1204831 were investigated in vitro and in vivo, using human cancer cell lines and mouse xenograft models.Results: EMD 1214063 and EMD 1204831 selectively suppressed the c-Met receptor tyrosine kinase activity. Their inhibitory activity was potent [inhibitory 50% concentration (IC50), 3 nmol/L and 9 nmol/L, respectively] and highly selective, when compared with their effect on a panel of 242 human kinases. Both EMD 1214063 and EMD 1204831 inhibited c-Met phosphorylation and downstream signaling in a dose-dependent fashion, but differed in the duration of their inhibitory activity. In murine xenograft models, both compounds induced regression of human tumors, regardless of whether c-Met activation was HGF dependent or independent. Both drugs were well tolerated and induced no substantial weight loss after more than 3 weeks of treatment.Conclusions: Our results indicate selective c-Met inhibition by EMD 1214063 and EMD 1204831 and strongly support clinical testing of these compounds in the context of molecularly targeted anticancer strategies. (c) 2013 AACR.