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

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.

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。

乳腺癌严重危害人类健康，转移和复发是其患者死亡的主要原因，靶向药物可为乳腺癌治疗提供新的策略，近年表明Myoferlin是乳腺癌转移的重要分子靶点。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；机理上，质谱和pull down 实验证明WJ460 和Myoferlin 结合，但是还不知道WJ460 的确切分子靶点、机制及其对乳腺癌复发的作用。本项目围绕WJ460 通过靶向Myoferlin 抑制乳腺癌转移和复发这一核心假设，探索WJ460 通过直接靶向Myoferlin抑制乳腺癌转移和复发的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有重要意义。