基于酪氨酸激酶和Wnt信号通路的多靶点抗癌药物发现

项目名称： 基于酪氨酸激酶和Wnt信号通路的多靶点抗癌药物发现

项目编号： No.21272144

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 李宝林

作者单位： 陕西师范大学

项目金额： 80万元

中文摘要： 以与癌密切关联的酪氨酸激酶和Wnt信号通路为靶点，发现具有喹唑啉母核的抗癌新化合物。包括①设计：用药物设计软件以喹唑啉母核为药效基团，在其上接入对Wnt信号通路有抑制作用的二苯乙烯结构单元和其它增效基团，建立虚拟化合物库。以酪氨酸激酶受体EGFR、VEGFR等及Wnt信号通路中的关键蛋白为靶点，将库中每个化合物与靶蛋白进行对接打分，对综合得分较高的新化合物进行化学合成。②合成：采用本实验室建立的新方法进行二苯乙烯类化合物的合成；通过Dimroth重排反应进行喹唑啉母核的形成及与二苯乙烯结构单元的连接，以合成得分较高的新化合物。③活性筛选：对合成的化合物通过体内外抗癌活性实验进行筛选，以获得低毒、高效的多靶点抗癌临床候选药物。④抗癌机理：以受试药物对EGFR、VEGFR、Axin2、β-catenin等在癌细胞中的表达和对EGFR、VEGFR活性的影响进行机理研究，以揭示其抗癌的作用规律。

中文关键词： EGFR；酪氨酸激酶抑制剂；喹唑啉类化合物；抗肿瘤；Western bloting

英文摘要： Tyrosine kinase and Wnt signaling pathway play an important role in development and tumorigenesis, and the deregulation of tyrosine kinase and Wnt signaling results in the formation of tumors. The project focuses on the discovery of new antitumor compounds with quinazolin moiety on the basis of tyrosine kinase and Wnt signaling pathway. The research includes mainly as follows: 1.The design and virtual screen of new compounds will be performed by using the computer assisted drug design. Several virtual compound databases will be established by introducing stilbene unit possessing the inhibition of Wnt signaling pathway to quinazolin scaffold with tyrosine kinase inhibited effect. New compounds will be screened through the docking the compound in virtual database to the active site of some important target proteins such as EGFR, VEGFR and the proteins expressed in Wnt signaling pathway. 2.Selected new compounds will be synthesized. Firstly, stilbene unit is constructed using a new method developed by our laboratory. Then, the formation of quinazolin scaffold and the introducing of stilbene unit will be done at the same time via Dimroth rearrangement reaction. 3.Synthesized compounds will be submitted to the determination of antitumor activities in vitro and vivo to find new antitumor agents. 4.Antitumor mechanis

英文关键词： EGFR；tyrosine kinase inhibitors；quinazoline derivatives；antitumor；Western bloting