Abstract：
The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.
摘要：
细胞间充质上皮转化因子（c-Met）是位于7q31基因座上的受体酪氨酸激酶（RTK），编码Met原癌基因，在调节细胞增殖中起关键作用，转移,分化,和凋亡通过各种信号通路。然而,它的异常激活和过表达与许多人类癌症有关。因此,c-Met是癌症治疗的有希望的靶标。然而,由于信号系统的复杂性以及不同蛋白质和酶的参与，选择性单靶向药物的抗癌作用受到限制。在抑制一条途径后，信号分子可以通过其他途径传播，导致单一靶向药物治疗效果不佳。同时阻断c-Met和另一个因子的双重抑制剂可以显着提高疗效并克服单靶标抑制剂的一些缺点，包括耐药性。在这次审查中,我们介绍了c-Met激酶以及c-Met与其他抗肿瘤靶点之间的协同作用。然后总结了基于c-Met治疗癌症的双靶点抑制剂，并详细讨论了它们的设计概念和结构-活性关系(SARs)，为进一步开发基于c-Met的新型双重抑制剂提供了有价值的见解。
