受体酪氨酸激酶c-Met在绝大部分的癌及部分肉瘤中高表达并异常激活，在肿瘤发生发展、侵袭转移、化疗抗性等各个环节均发挥关键作用。不同于其他激酶，c-Met作为肿瘤信号网络通路中的关键节点蛋白，可以与细胞表面其他激酶、受体相互作用而备受关注。特别是，MET基因扩增与20%的EGFR-TKIs获得性耐药密切相关，因此寻找新颖高效的c-Met抑制剂已成为医药界研究的前沿热点。
上海药物所药物化学课题组和肿瘤药理课题组研究人员通力合作，通过合理的药物设计和结构优化，发现了一类选择性地靶向受体酪氨酸激酶c-Met的多取代喹啉衍生物，其在分子水平对c-Met酶活抑制高达0.95 ± 0.13 nM，与已报道的高活性化合物相当。进一步研究表明，这类化合物对c-Met活化介导的下游关键信号通路以及c-Met依赖性肿瘤细胞株的增殖具有明显的抑制作用。同时，体内结果显示，该化合物对HGF诱导的c-Met依赖性人神经胶质瘤U87-MG裸小鼠移植瘤和非HGF依赖性的NIH3T3/TPR-Met裸小鼠移植瘤的生长均具有明显的抑制作用。 这一研究结果不仅为进一步研究c-Met介导的生物功能提供了一类全新的分子探针，同时为开发具有我国自主知识产权抗肿瘤药物提供了一类潜力较好的药物先导物。
研究成果最近发表在《Journal of Medicinal Chemistry》 (2011, 54：2127-2142)上。文章发表第二天即收到美国Calbiochem公司要求购买并商品化该产品的请求。同时，SciBX (The Science Business eXchange， 是由Nature出版社推出的，以分析生命科学领域最具商业潜力的学术文献为内容的电子期刊) 也把这一工作作为本周新闻进行报道（http://www.nature.com/scibx/journal/v4/n13/pdf/scibx.2011.363.pdf）。（生物谷Bioon.com）
生物谷推荐原文出处：
J. Med. Chem., 2011, 54 (7), pp 2127–2142 DOI: 10.1021/jm101340q
Synthesis and c-Met Kinase Inhibition of 3,5-Disubstituted and 3,5,7-Trisubstituted Quinolines: Identification of 3-(4-Acetylpiperazin-
1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a Novel Anticancer Agent
Yuanxiang Wang?, Jing Ai?, Ying Wang?, Yi Chen?, Lu Wang?, Gang Liu?, Meiyu Geng*?, and Ao Zhang*?
By use of an improved synthetic strategy, a series of 3,5-disubstituted and 3,5,7-trisubstituted quinolines were readily prepared. 3,5,7-Trisubstituted quinolines 21a?c, 21l, and 27a?c were identified as the most potent c-Met inhibitors with IC50 of less than 1.0 nM. Compound 21b showed the most promising overall PK profile and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron and 12 other tyrosine kinases. It produced constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition (68?69%) in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Its favorable in vitro and in vivo profiles warrant further investigation.
