Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
J Med Chem. 2012 Mar 8;55(5):1858-67. doi: 10.1021/jm201330u. Epub 2012 Feb 24.
Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.
c-Met 受体酪氨酸激酶活性的失调导致动物模型中的肿瘤发生和转移。更重要的是，c-Met 中的激活突变的鉴定以及人类癌症中 MET 基因扩增表明 c-Met 是癌症治疗的重要靶点。我们之前描述了两类 c-Met 激酶抑制剂（I 类和 II 类），它们在结合模式和选择性特征上有所不同。II 类抑制剂往往对多种激酶具有活性。这些分子在 c-Met 蛋白中的结合模式的知识导致了几种新的 II 类 c-Met 抑制剂的设计和评估，这些抑制剂利用各种 5 元环羧酰胺来构象约束分子内的关键药效团。这些研究导致了具有良好体内活性的新型强效吡唑啉酮 c-Met 抑制剂的鉴定。
