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

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.