新的小分子化合物YH-8306靶向Arp2/3抑制结肠癌生长和转移的分子机理研究

结肠癌发病率和死亡率均呈上升趋势，严重危害人类健康，结肠癌患者死亡的主要原因是肿瘤转移和复发。在结肠癌相关分子机理中，actin 相关蛋白复合物Arp2/3与肿瘤转移密切相关，是重要的分子靶点。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化合物并研究其功能和机制意义重大。通过筛选，申请者已经发现一种新的合成小分子化合物YH-8306体外抑制结肠癌细胞的生长、克隆形成、迁移和粘附，并诱导其凋亡；进一步发现它抑制结肠癌移植瘤的生长；YH-8306还可以调节Arp2/3的细胞定位和活性，计算机模拟发现YH-8306可以和Arp2/3结合，但是尚不清楚YH-8306的确切靶点及其对结肠癌转移和复发的作用。本项目围绕核心假设-YH-8306靶向Arp2/3抑制结肠癌生长和转移，研究YH-8306抗结肠癌的新功能和新机理。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。

Colorectal cancer seriously harms human health because its incidence and mortality rates show an upward trend. The leading causes of death are metastasis and recurrence of colorectal cancer. In the mechanism involved in colorectal cancer progression,actin-related protein 2/3 complex (Arp2/3)is the important molecular target because of its critical roles in tumor metastasis. Small molecule compound is the important source of new drug research and development. Therefore, it is very significant to identify new small molecules targeting Arp2/3 and study the functions and mechanisms. Before application, we had screened and found a new small molecule compound, YH-8306, not only inhibited colorectal cancer cell proliferation, colony formation, migration and adhesion but also induced apoptosis of colorectal cancer cell in vitro. Furthermore, YH-8306 inhibited tumor growth in colorectal cancer xenograft model. We also found that YH-8306 suppressed cellular localization and activity of Arp2/3. Computer docking assay showed that YH-8306 directly bond to Arp2/3. However, the direct target and the role of YH-8306 in colorectal cancer metastasis and recurrence is still unknown. In this project, we provide the hypothesis that YH-8306 inhibit colorectal cancer growth， metastasis and recurrence by targeting Arp2/3. We will further reveal the new functions and mechanisms of YH-8306 in colorectal tumor metastasis and recurrence. This project is important for elucidating the anti-tumor mechanism by small molecule compound and discovering new drugs.