靶向c-Met的Ⅰ型小分子抑制剂的研究进展

Research Progress of Type Ⅰ Small Molecular Inhibitors for Targeting c-Met

间质–表皮转化因子(cellular-mesenchymal epithelial transition factor,c-Met)为受体酪氨酸激酶(receptor tyrosine kinases,RTKs)亚家族的一个原型成员,也是目前已知的唯一肝细胞生长因子(hepatocyte growth factor,HGF)受体。在正常生理条件下,c-Met/HGF信号通路在调控细胞增殖、运动、迁移和侵袭等多过程中起着至关重要的作用。然而这一信号通路的异常激活已成为细胞癌变的驱动性因素。此外,c-Met/HGF信号通路的失调也被证明与临床疗效和耐药相关。因此,c-Met/HGF信号通路作为抗癌药物的新靶点备受关注。现已有多种策略用于调控c-Met/HGF的异常激活,其中小分子c-Met抑制剂因有大量化合物进入临床或上市而备受注目。因Ⅰ型c-Met抑制剂与ATP位点结合时在Met1211残基周围形成"U"型构象,这种特殊的结合模式使Ⅰ型抑制剂比Ⅱ型抑制剂对c-Met更具选择性。因此,该文就c-Met/HGF信号通路在肿瘤中的作用及Ⅰ型小分子c-Met抑制剂的药物化学和临床研究进展作一综述。

c-Met (cellular-mesenchymal epithelial transition factor) is a prototype member of a subfamily of heterodimeric RTKs (receptor tyrosine kinases) and is the only known receptor for HGF (hepatocyte growth factor) till now.Under normal physiological conditions,the c-Met/HGF signaling pathway is crucial in mediating various cellular processes including proliferation,motility,migration and invasion,etc.However,aberrant activation of this signalling pathway has frequently been found as the driving factor in human cancers.Moreover,dysregulation of c-Met/HGF signalling has also demonstrated which is associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies.Consequently,c-Met has emerged as a promising target for cancer drug development.Up to now,many strategies have been applied to modulate c-Met/HGF signaling pathway in human clinical studies for the treatment of cancer,and small molecule c-Met inhibitors have draw the most attention from the pharmaceutical industry due to a considerable number of compounds entering clinical trials or being marketed as anticancer drugs.Because type Ⅰ c-Met inhibitors commonly bind to the entrance of ATP-binding site in “U” shape,this binding mode makes type Ⅰ c-Met inhibitors more selective than that of type Ⅱ inhibitors.This review provides an overview of c-Met/HGF signaling pathway in cancer and reviews the recent advancements in medicinal chemistry development and clinical applications of type Ⅰ small molecule c-Met inhibitors.