Fazio, Nicholas; Russell, Michael; Krapohl, John; Andrus, Brayden; Hansen, Marc (Brigham Young University)
Faculty Advisor: Hansen, Marc (Brigham Young University, Physiology and Developmental Biology)
PIM 3 is a proto-oncogene with serine/threonine kinase activity that can prevent apoptosis, promote cell survival and protein translation. Abnormal PIM3 activity contributes to tumorigenesis by phosphorylation of targets that release anti-apoptotic proteins. Pathological PIM3 expression is common in pancreatic and prostate cancer. Inhibiting this kinase activity can be used to therapeutically suppress uncontrolled cell growth in cancerous tissues. Synthetic inhibitors are being developed as therapeutics to treat PIM3 related disorders. Compounds derived from plants and natural sources have therapeutically-relevant biological activity. Additionally, they often well tolerated, making them important starting points for drug discovery efforts. A less widely used approach to discover the biological activity of molecules is built around using a large scale in-silico molecular screening, which has emerged as a critical drug discovery tool. Here, we screen a large (>100,000 compound) virtual library of natural product compounds for binding in the PIM3 ATP binding site, then validate compounds with using cell-based and immuno-based assays. This approach reveals PIM3 inhibition by a saponin scaffold, which suggests potential utility as a therapeutic or as a lead for further optimization.