新的小分子化合物WJ460通过靶向Myoferlin抑制乳腺癌转移和复发的分子机理研究

项目名称： 新的小分子化合物WJ460通过靶向Myoferlin抑制乳腺癌转移和复发的分子机理研究

项目编号： No.81472788

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： 易正芳

作者单位： 华东师范大学

项目金额： 72万元

中文摘要： 乳腺癌发病率呈上升趋势，严重危害人类健康。转移和复发是乳腺癌患者死亡的主要原因，分子靶向药物可为乳腺癌治疗提供新的有效策略，近年的研究表明，Myoferlin是乳腺癌转移相关的重要分子靶点。小分子化合物是新药研发的重要源泉，鉴定新的靶向小分子并研究其功能和机制具有重要意义。申请者通过前期筛选发现一种新的小分子化合物WJ460抑制乳腺癌细胞的迁移和侵袭，在小鼠实验性和自发性转移模型中，WJ460显著抑制乳腺癌转移；机理研究上，质谱和pull down实验显示WJ460可以和Myoferlin结合，但是尚不清楚WJ460的确切作用靶点、分子机制及其对乳腺癌复发的影响。本项目围绕核心假设-WJ460通过靶向Myoferlin抑制乳腺癌转移和复发，研究WJ460通过直接靶向Myoferlin抑制乳腺癌转移和复发的新功能和新的分子机理。本课题对阐明小分子化合物抗肿瘤的分子机制及新药研发具有重要意义。

中文关键词： C21_乳腺肿瘤；小分子化合物；转移和复发；靶向；Myoferlin

英文摘要： Breast cancer seriously harms to human health because its incidence showed an upward trend. Metastasis and recurrence of breast cancer are the leading cause of death. Target therapy is a new and effective strategy for breast cancer. Recent reports showed that Myoferlin was an important molecular target involved in breast cancer metastasis. Small molecule compounds are an important source of new drug research and development. Therefore, it is very significant to identify new small molecules targeting Myoferlin and study the functions and mechanisms. Before application, we had screened and found a novel small molecule compound, WJ460, which inhibited breast cancer cell migration and invasion in vitro. Furthermore, WJ460 inhibit the metastasis of breast cancer in experimental and spontaneous breast tumor metastasis models. As for molecule mechanism， we found that WJ460 bound to Myoferlin in mass spectrometry and pull down assays. However, the direct target, mechanism and the roles of WJ460 in breast cancer metastasis and recurrence are still unknown. In this project, we provid the hypothesis that WJ460 inhibits breast cancer metastasis and recurrence by directly targeting the Myoferlin. We will further reveal the new functions and mechanisms of WJ460 in breast cancer metastasis and recurrence. This project is important for elucidating the anti-tumor mechanism of small molecule compounds and discovering new drugs.

英文关键词： breast caner;small molecule;metastasis and recurrences;target;Mroferlin