Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY/ABSTRACT Glycogen synthase kinase-3 (GSK-3) is a highly active kinase that has been implicated in a variety of pathologies including neurodegenerative diseases, metabolic disorders, cancer, and conditions involving a dysfunctional innate immune response. Thus, there is an ongoing, intense effort aimed at developing inhibitors of GSK-3. Despite these endeavors, no specific GSK-3 inhibitor is currently on the market. There remains, therefore, a critical need for the development of new GSK-3-specific compounds that would be effective at treating diseases caused by aberrant GSK-3 activity. Our long-term research goal is to discover and develop safe, and cost effective, GSK-3-specific inhibitors that can be used as therapeutic agents in the treatment of human disease. We have identified a novel small organic compound, COB-187, that exhibits potent and selective inhibition of GSK-3 in molecular assays and inhibits cellular GSK-3 activity. Our central hypothesis is that a class of compounds, termed I-GSK-3s and exemplified by COB-187, represent a novel chemical scaffold upon which highly potent and selective GSK-3 inhibitors can be designed. We will complete the following specific aims that will elucidate the mechanism of action of the I-GSK-3s and probe their potential as therapeutics for pathologies involving a dysfunctional innate immune response. First, we will determine if I-GSK-3s inhibit GSK-3 via a specific, relatively slow reversible mechanism involving a cysteine residue in the active site of GSK-3. The results of these studies will be incorporated into our ongoing in silico work aimed at refining the chemical definition of I-GSK-3s. Second, we will determine the ability of the I-GSK- 3s to attenuate viral and bacterial-associated molecular pattern-induced overexpression of cytokines. This latter aim will give insight into the ability of the I-GSK-3s to abate cytokine storms that are germane to several life- threatening conditions. Compounds represented by this novel chemical scaffold have the potential to become therapeutics for disease processes involving aberrant GSK-3 activity. The proposed work will provide a strong scientific foundation for the development of such therapeutics. Thus, successful completion of these studies will have a positive impact on a host of human pathologies including conditions involving a dysfunctional innate immune response.
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