中国学者发现肿瘤蜗牛蛋白靶向抑制剂

　　在众多的肿瘤靶点之中，有两个以软体动物命名的靶点（蜗牛蛋白、鼻涕虫蛋白）都参与了肿瘤转移。其中，蜗牛蛋白是由SNAI1基因编码的锌指转录因子，高表达于乳腺癌等人类肿瘤，可以促进肿瘤生长和转移。因此，蜗牛蛋白靶向抑制剂有望对乳腺癌患者带来治疗获益。不过，传统认为蜗牛蛋白“无药可靶”，并且亦未发现有效的靶向抑制剂。

　　2020年4月22日，美国科学促进会《科学》旗下《科学进展》发表中国药科大学、南京医科大学第一附属医院（江苏省人民医院）的研究报告，发现小分子化合物CYD19可以有效抑制蜗牛蛋白，从而抑制肿瘤的生长和转移。

　　该研究发现，这种小分子化合物CYD19可以与蜗牛蛋白第174位精氨酸口袋状结构形成高度亲和的相互作用。对于浸润癌细胞，CYD19可以与蜗牛蛋白结合，从而破坏蜗牛蛋白与肿瘤转录因子CBP/P300的相互作用，从而削弱CBP/P300引起的蜗牛蛋白乙酰化，随后被泛素和蛋白酶降解。此外，体外和体内研究表明，CYD19可以通过蜗牛蛋白恢复肿瘤抑制蛋白P53对肿瘤细胞的抑制，从而抑制肿瘤生长和存活。而且，CYD19可以逆转蜗牛引起的上皮→间质转化，进一步抑制上皮→间质转化引起的肿瘤浸润和转移。

　　因此，该研究结果表明，通过小分子化合物CYD19靶向抑制蜗牛蛋白，可能对乳腺肿瘤患者产生有效的治疗作用，故有必要开展进一步临床研究进行验证。

Sci Adv. 2020 Apr 22;6(17):eaaw8500.

A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer.

Hong-Mei Li, Yan-Ran Bi, Yang Li, Rong Fu, Wen-Cong Lv, Nan Jiang, Ying Xu, Bo-Xue Ren, Ya-Dong Chen, Hui Xie, Shui Wang, Tao Lu, Zhao-Qiu Wu.

China Pharmaceutical University, Nanjing, China; The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered "undruggable", and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail's interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

DOI: 10.1126/sciadv.aaw8500