Introduction: Degradation of surrounding matrix components by secreted proteolytic enzymes play an important role in the development of various malignant tumors. Recent study indicate that cathepsin S, the crucial cysteine protease, is p-regulated in pancreatic and other tumors and secreted into the extracellular milieu for extracellular matrix degradation. Aims: We designed and generated a series of cathepsin S inhibitors to test their anti-proliferative activity against pancreatic cancers and study their mechanism of action. Materials & methods: A series of new synthesized small molecule compounds which bearing an a -ketoamide warhead were evaluated their inhibitory ability against cathepsin S. Kinetic analysis were used to reveal the Ki values and specificities. Several pancreatic cell lines were used to test anti-proliferative activity of these compounds. Cell invasive and migratory assays were also performed Orthotopic animal model were used to determine the antitumor effect in vivo. Results: We characterized a novel a -ketoamide inhibitor which exerts low Ki values and high specificity against cathepsin S activities. Targeting cathepsin S could induce autophagy followed by ROS generation and trigger cell apoptosis. Inhibiting cathepsin S activities not only reduces fibronectin degradation but also attenuates the migration and invasive abilities in various pancreatic cell lines. The results of the effect of candidate compound showed that a novel cathepsin S inhibitor can effective reduce the spread of pancreatic tumor cells and consequently prolong mice survival in orthotopic animal model. Conclusion: These results suggest that cathepsin S inhibitor could have potential as antitumor agent against pancreatic cancer.
