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

• Published in: Journal of medicinal chemistry Vol. 62; no. 10; pp. 4949 - 4966
• Main Authors: Li, Yunqi, He, Yuan, Shao, Ting, Pei, Haixiang, Guo, Weikai, Mi, Dazhao, Krimm, Isabelle, Zhang, Yuanjin, Wang, Peili, Wang, Xin, Liu, Mingyao, Yi, Zhengfang, Chen, Yihua
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.05.2019; Amer Chemical Soc
• Subjects: Chemical Sciences; Chemistry, Medicinal; Life Sciences & Biomedicine; Medicinal Chemistry; Pharmacology & Pharmacy; Science & Technology; CYTOCHROME-P450; METABOLISM; IDENTIFICATION; EXPRESSION; GROWTH
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00059

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 targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis.