肿瘤细胞的扩散是癌症导致人类死亡的最主要的因素。我们的前期工作以抑制乳腺癌细胞扩散为靶点，针对在乳腺癌细胞扩散中起重要作用的E3泛素连接酶Smurf1进行了高通量的抑制剂筛选，成功地得到了能够有效抑制Smurf1活性的小分子抑制剂，并且在细胞水平初步验证了其细胞生物学活性，证实该小分子抑制剂的确能够有效地抑制转化生长因子（TGFbeta）诱导的乳腺上皮细胞的上皮-间质细胞的转化过程（EMT）和细胞的迁移能力。在此基础上，我们将进一步在细胞水平以及动物模型上对该小分子抑制剂在抑制乳腺癌细胞扩散中的作用进行系统深入的研究。我们将以该小分子抑制剂为模板，对其进行修饰改造以得到其衍生物的化合物库，并对其进行结构与功能关系的研究，以阐明其对Smurf1抑制的分子机理，并对其进行优化以得到能够用于新的抗乳腺癌药物研发的先导化合物。

Tumor cell metastasis is the major cause of death of cancer patients. In our previous study, we developed a cell-based high-throughput screen system for screening modulators of E3 ubiquitin ligases. Taking advantage of this screening system, we successfully identified a specific inhibitor for E3 ubiquitin ligase Smurf1, a key regulator in metastasis by controlling TGFbeta-induced epithelial-to-mesenchymal transition (EMT) of mammary epithelial cells through targeting RhoA for degradation. Indeed, treatment of this small molecule significantly blocked TGFbeta-induced mammary epithelial cell EMT, cellular protrusive activity, and cell migration, confirming that this compound is an effective inhibitor for Smurf1. Therefore, we will further systematically investigate the effect of this Smurf1 inhibitor on blocking breast cancer cell invasive activity and tumor metastasis on cellular level and using mouse models. We will generate a compound library of derivatives of this Smurf1 inhibitor to study its structure-activity relationship and elucidate the mechanism for inhibition of Smurf1 by the inhibitors, therefore providing a promising lead compound for breast cancer therapy by targeting tumor metastasis.