基于肿瘤干细胞标志物APN/CD13为靶标的抗癌先导物的发现

肿瘤干细胞的存在被认为是引起肿瘤复发和转移的重要原因之一。研究证明APN/CD13是肝癌干细胞的生物标志物，在肝癌的复发和转移中发挥着重要作用。本课题借助多学科交叉的优势，利用分子动力学模拟，获得人源APN与其抑制剂探针分子结合位点更精确的结构信息。再根据hAPN与其抑制剂Bestatin晶体结构揭示的三维结合模式，进行合理药物设计、定向合成，构建具有结构多样性的小分子化合物库，然后进行分子水平抑酶活性筛选和细胞、动物水平的抗癌活性评价。通过获得三维定量构效关系和高活性化合物与酶的共结晶复合物培养及结构解析，指导下一轮的分子设计和结构优化。经过几轮筛选后，期望能发现活性良好的抗肿瘤先导化合物，为研究开发具有自主知识产权的抗癌药物奠定基础。

Cancer stem cell plays an important role in the tumor recurrence. Aminopeptidase N(APN/CD13), one of liver cancer stem cell markers, is closely associated with the recurrence and metastasis of liver cancer. We will obtain the more precise structure information of the compound binding site of the human APN by molecular dynamic simulations. Taking the advantage of multidiscipline, we design and synthesize the diverse small molecules. All the small molecules will be assayed in the enzymatic level, cellular level and animal level. Then we obtain the three-dimension quantitative structure-activity relationship and the co-crystallized complex of activity compounds and human APN. After several rounds of screening, we will maybe able to find a lead compound with the satisfactory anti-tumor activity. We expect to lay the foundation for research and development of new drugs.