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The serine threonine kinase glycogen synthase kinase-3 (GSK-3) is a promising drug discovery target in diverse pathological disorders. GSK-3 was initially implicated in glycogen metabolism, however, the enzyme has surprised us with a host of additional regulated processes related to other disease states including cancer, psychiatric disorders, and neurodegenerative diseases. Indeed, treatment with GSK-3 inhibitors produces significant therapeutic benefits in multiple disease-animal models. How one enzyme can be involved in such diverse processes is not fully clear. It is possible that common targets regulated by GSK-3 have different biological impacts in different tissues and/or different cellular conditions.
To tackle this problem we use cell systems that either overexpress GSK-3 or inhibit its activity selectively and screen for potential downstream factors in a ‘hypothesis free’ approach. Our studies identified the mammalian target of rapamycin (mTOR) as a GSK-3 target. Accordingly GSK-3 was found to regulate autophagy and lysosomal acidification. These findings suggested a new paradigm in which GSK-3 serves as a molecular switch of biosynthesis and protein turnover. Hence, inhibition of GSK-3 re-balances protein homeostasis, often impaired in pathogenesis, which in turn ameliorates disease severity and disease progression.
An additional, and complementary, aspect of our work is development of selective GSK-3 inhibitors. We developed a pipeline of substrate competitive GSK-3 inhibitors that show high selectivity and excellent pharmacological properties. The strategy for design of selective GSK-3 inhibitors and screening for potential new inhibitors will be also discussed.