假白榄烷型大环二萜类化合物抗非小细胞肺癌EGFR-TKIs获得性耐药的作用机制和构效关系研究

项目名称： 假白榄烷型大环二萜类化合物抗非小细胞肺癌EGFR-TKIs获得性耐药的作用机制和构效关系研究

项目编号： No.81473119

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张维库

作者单位： 中日友好医院

项目金额： 70万元

中文摘要： 获得性耐药问题严重制约了EGFR酪氨酸激酶抑制剂（EGFR-TKIs）在临床上治疗非小细胞肺癌（NSCLC）的广泛使用，EGFR T790M突变和Met基因扩增是导致其获得性耐药的重要机制。我们前期发现来源于大戟属植物的假白榄烷型大环二萜类成分对吉非替尼敏感和耐药NSCLC细胞以及小鼠移植瘤均具有显著的抑制活性，初步的作用机制研究表明其能够抑制耐药EGFR及c-Met蛋白的磷酸化。本项目拟进一步对3种大戟属植物中的假白榄烷型化合物进行分离、鉴定、富集和结构修饰，采用单独或联合用药评价其对多种敏感或耐药的NSCLC细胞和小鼠移植瘤的活性，利用western-blot等分子生物学技术探讨其抗耐药的作用靶点和作用机制，同时利用分子对接方法研究活性化合物与耐药靶蛋白之间的结合位点和构效关系。本研究将为EGFR-TKIs获得性耐药NSCLC新型治疗药物先导化合物的发现提供科学依据。

中文关键词： 假白榄烷二萜；非小细胞肺癌；获得性耐药；作用机制；构效关系

英文摘要： EGFR-TKIs have been proved good therapy in NSCLC, but acquired resistance limits its clinical use. It is hot point for R&D of EGFR-TKIs how to overcome acquired resistance. EGFR T790 mutant and Met amplification are main reasons that result in acquired resistance of EGFR-TKIs. Our previous studies proved that several new jatrophane diterpenes from Euphorbia sororia and Euphorbia turczaninowii showed marked inhibitory activities against NSCLC cell lines. The primary mechanism showed that jatrophane diterpenes overcome resistance of cancer cells by inhibiting phosphorylation of EGFR and c-Met. In the project,more jatrphane diterpenes from Euphorbia genus are to isolated and synthesized; Inhibitory activities against cancer cells are evaluated in vivo and in vitro; Pharmacological EGFR-TKIs-resistant mechanisms are determined; In addition,action sites and structure-activity relativity are presented on the basis of molecular docking and computer aided drug design. The results provide scientific facts for discovery of new leding compounds of NSCLC drugs.

英文关键词： jatrophane diterpene;non-small-cell lung cancer;acquired resistance;action machanism;structure-activity relationship