恶性肿瘤的远端转移是肿瘤临床治疗亟待解决的关键问题。锌指转录因子Snail在多种恶性肿瘤中高表达，与肿瘤转移和不良预后密切相关。迄今，直接靶向Snail蛋白的有效抑制剂未见文献报道。因此，我们设计、合成并筛选了全新结构的CYD系列化合物。前期研究发现，CYD19与Snail蛋白174位精氨酸形成稳定结合，继而干扰CBP/p300-Snail蛋白互作，使Snail蛋白失去乙酰化保护而促进其泛素化降解。CYD19通过抑制Snail/p53-wt信号通路而抑制p53野生型肿瘤细胞增殖，也通过逆转Snail诱导的上皮-间质转化而以p53非依赖的形式抑制肿瘤细胞侵袭及转移。本项目拟在前期研究的基础上，进一步明确CYD19为CBP/p300-Snail蛋白互作小分子抑制剂，并应用多种细胞和动物模型阐明CYD19抗肿瘤增殖及转移的药理学作用及分子机理。本研究将为开发新型抗肿瘤转移的靶向药物提供新的思路。

The distal metastasis of malignant tumors is a key issue in cancer therapy. The zinc-finger transcription factor Snail is inappropriately expressed in various types of malignant tumors, and its expression levels are positively associated with tumor metastasis and poor prognosis. So far, no effective pharmacological inhibitor that directly targets Snail protein is reported in literatures. Accordingly, we designed, synthesized and screened a serial of “CYD” small-molecule compounds. Preliminary studies have shown that CYD19 forms a high-affinity interaction with the arginine 174 pocket of Snail protein and thus interrupts Snail’s interaction with CBP/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. We further discover that CYD19 significantly inhibits growth of tumor cells harboring wild-type p53 via decreasing Snail/p53-wt signaling pathway. On the other hand, CYD19 suppresses tumor invasion and metastasis in a p53 independent fashion by reversing Snail-induced epithelial-mesenchymal transition. Based on these preliminary observations, we propose the following studies: 1) to further confirm CYD19 as a novel CBP/p300-Snail interaction inhibitor; 2) To investigate the anti-tumor effect of CYD19 and the underlying molecular mechanism using a variety of in vitro and in vivo models. These studies should shed a light on the development of novel small-molecule compounds that specifically target tumor metastasis.