Modification and Biological Evaluation of a Series of 1,5-Diaryl-1,2,4-triazole Compounds as Novel Agents against Pancreatic Cancer Metastasis through Targeting Myoferlin
Modification and Biological Evaluation of a Series of 1,5-Diaryl-1,2,4-triazole Compounds as Novel Agents against Pancreatic Cancer Metastasis through Targeting Myoferlin
复制标题
一系列 1,5-二芳基-1,2,4-三唑化合物作为通过靶向肌铁蛋白抗胰腺癌转移的新药物的修饰和生物学评价。
DOI：
10.1021/acs.jmedchem.9b00059
复制
发表时间：
2019-05-23
影响因子：
7.3
通讯作者：
Chen, Yihua
中科院分区：
文献类型：
--
作者：
Li, Yunqi;He, Yuan;Chen, Yihua
胰腺癌是最常见的癌症之一，生存率极低。胰腺癌患者在诊断时发现转移是癌症相关死亡的主要原因之一，超过50%的胰腺癌患者存在转移。迫切需要新的治疗靶点和阻断肿瘤转移的药物。在此，我们报道了一系列1,5-二芳基-1,2,4-三唑衍生物作为有效的抗转移剂。先导化合物6y在体外和体内均显示出有效的抗胰腺癌转移活性。相关研究表明，6y可能与myoferlin （MYOF）结合，MYOF是一种新的潜在抗肿瘤转移靶点，可调节囊泡运输和转移相关蛋白。随后的生物物理和生化方法证实6y与MYOF结合。机制研究表明，6y通过逆转上皮间质转化、抑制基质金属蛋白酶分泌和阻断受体酪氨酸激酶抑制胰腺癌转移。我们的研究结果表明，用6y靶向MYOF可能是一种有希望的治疗策略，以防止胰腺癌转移。
Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein, we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent antimetastatic agents. Lead compound 6y displayed effective antimetastatic activities in pancreatic cancer in vitro and in vivo. Concomitant studies indicated that 6y probably binds with myoferlin (MYOF), a novel potential antitumor metastasis target, which regulates vesicle trafficking and metastasis-related proteins. Subsequent biophysical and biochemical methods verified that 6y bound to MYOF. Mechanism studies revealed that 6y inhibited pancreatic cancer metastasis through reversing the epithelial mesenchymal transition, inhibiting the secretions of matrix metalloproteinase and blocking the receptor tyrosine kinases. Our findings suggest that that targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis.