肿瘤转移是肿瘤致死的主要原因之一。而上皮细胞-间充质细胞转化（EMT）是肿瘤转移过程中最显著的特征之一，TGFbeta信号转导通路在肿瘤EMT过程中扮演着至关重要的作用。通过靶向TGFbeta受体激酶，借助于结构优化，前期研究发现了一类靶向TGFbeta受体激酶抑制活性的四氢-beta-咔啉类化合物，研究结果表明此类化合物对癌细胞的迁移和体内小鼠肿瘤转移都有显著的抑制作用。本项目拟在前期关于四氢-beta-咔啉类化合物结构优化的基础上，设计、合成新型用于抗肿瘤转移的药物先导化合物：（1）设计、合成不同位置取代的四氢-beta-咔啉类化合物，并总结此类化合物较为明确的构效关系；（2）确认此类化合物与TGFbeta受体激酶及下游信号转导通路的分子作用机制与模式；（3）选择体外综合评价最高的化合物进行抗肿瘤转移动物模型的效果检测，最终获得基于靶向TGFbeta受体激酶的抗肿瘤转移药物先导化合物。

Tumor Metastasis, one of the main reasons of cancer death, is account for about 90% of cancer death. Epithelial-mesenchymal transition (EMT) is one of the most striking features in the process of tumor metastasis, and the transforming growth factor beta (TGFbeta) signal transduction pathway can regulate cell proliferation, division, adhesion, migration, invasion angiogenesis and immune suppression, which indicated that TGFbeta signal pathway plays a crucial role in the process of tumor EMT. Our preliminary study have been shown that one novel type of tetrahydro-beta-cabolines compounds were discovered based on targeted TGFbeta receptor kinase by means of assay screening followed by structure optimizaition. The results indicated that such compounds have a very effective inhibition of cancer cell migration and tumor metastasis in mice. The project is planned to design and synthesize novel drug lead compounds against tumor metastasis on the basis of structure optimization of tetrahydro-beta-carboline compounds through targeted TGFbeta Receptor type I kinase: (1) A series of substitution on different positions of tetrahydro-beta-carboline compounds would be designed and synthesized, and the more detailed structure-activity relationship of these compounds would be summarized; (2) the mechanism and mode of these compounds would be confirmed with TGFbeta receptor kinase and downstream signal transduction pathway; (3) Compounds with most potent effect in vitro would be selected for inhibitory evaluation on an animal model of tumor metastasis, and finally the lead compounds against tumor metastasis was afforded through targeting TGFbeta receptor kinase.