Zhang Jin, Jiang Xiangdong, Jiang Yingnan, Guo Mingrui, Zhang Shouyue, Li Jingjing, He Jun, Liu Jie, Wang Jinhui, Ouyang Liang
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Department of Information Engineering, Chongqing Vocational Institute of Safety Technology, Chongqing, 404020, China.
Eur J Med Chem. 2016 Jan 27;108:495-504. doi: 10.1016/j.ejmech.2015.12.016. Epub 2015 Dec 13.
Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
血管内皮生长因子受体（VEGFR）是一种非常重要的受体酪氨酸激酶（RTK），它可诱导血管生成、促进细胞生长和转移、减少细胞凋亡、改变细胞骨架功能并影响其他生物学变化。此外，已发现在多种人类癌症中VEGFR失调。因此，VEGFR成为临床试验中多种重要抗癌药物的显著靶点。另一方面，c-Met是肝细胞生长因子（HGF）的受体，也是一种受体酪氨酸激酶。先前的研究表明，c-Met可引发许多不同的信号通路，介导细胞增殖、迁移、分化和存活。此外，HGF/c-Met通路异常信号与肿瘤侵袭性生长、癌症患者预后不良之间的相关性已得到证实。最近的报告显示，c-Met/HGF和VEGFR/VEGF（血管内皮生长因子）在许多疾病的进展中可协同作用。它们还被发现在许多人类癌症中过度表达。因此，在多种恶性肿瘤中，VEGFR和c-Met受体酪氨酸激酶已成为治疗靶点。随着分子生物学技术的发展，对人类肿瘤疾病发病机制以及肿瘤细胞相关信号通路的进一步了解，使用单一靶点抑制剂已难以达到理想的治疗效果。此时，相对于两种抑制剂联合使用，一种能够同时抑制VEGFR和c-Met的单一化合物可能具有提高抗癌活性的优势。鉴于对这些化合物的浓厚兴趣，本综述重新审视了先前关于开发双靶点VEGFR和c-Met小分子抑制剂作为新型抗癌药物的研究工作。新收集的衍生物主要描述了它们的生物学特性和化学结构。
