Department of Medicinal Chemistry, UCB Celltech, 216 Bath Road, Slough SL1 3WE, United Kingdom.
Expert Opin Ther Pat. 2010 Feb;20(2):159-77. doi: 10.1517/13543770903514137.
c-Met kinase is the receptor for hepatocyte growth factor. Primarily expressed on epithelial and mesenchymal cells its normal function is associated with wound healing, liver regeneration and embryo development. However, dysregulation of c-Met through overexpression, gene amplification, mutation or a ligand-dependent autocrine/paracrine loop is associated with tumorigenesis. c-Met dysregulation in human cancer patients is typically associated with a poor prognosis, aggressive disease, increased metastasis and shortened patient survival. Targeting the hepatocyte growth factor/c-Met signalling pathway as a means of cancer therapy has, therefore, become increasingly popular with a number of different therapeutic approaches undergoing clinical trials. AREAS COVERED BY THIS REVIEW: This review covers the patent applications for small molecule c-Met kinase inhibitors since 2007, attempts to place them in context from a structural point of view and examines their potential applications in cancer therapy.
Readers will gain an overview of the structural types of c-Met inhibitors, the major players in the field and an insight into what is progressing into the clinic.
This area is developing rapidly and the results of the various ongoing clinical trials will generate an increased understanding of the potential benefits and pitfalls of c-Met inhibitors as therapeutic agents.
c-Met 激酶是肝细胞生长因子的受体。主要表达于上皮细胞和间充质细胞，其正常功能与创伤愈合、肝再生和胚胎发育有关。然而，c-Met 通过过表达、基因扩增、突变或配体依赖性自分泌/旁分泌环的失调与肿瘤发生有关。人癌症患者的 c-Met 失调通常与预后不良、侵袭性疾病、转移增加和患者生存时间缩短有关。因此，靶向肝细胞生长因子/c-Met 信号通路作为癌症治疗的一种手段越来越受到关注，许多不同的治疗方法正在进行临床试验。本综述涵盖了自 2007 年以来小分子 c-Met 激酶抑制剂的专利申请，试图从结构角度对它们进行定位，并探讨它们在癌症治疗中的潜在应用。读者将获得 c-Met 抑制剂的结构类型概述、该领域的主要参与者，并深入了解正在进入临床的情况。这一领域发展迅速，各种正在进行的临床试验的结果将提高人们对 c-Met 抑制剂作为治疗剂的潜在益处和陷阱的认识。
