Novel Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Therapeutic Agents - 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. Our central hypothesis is that the class of compounds exemplified by COB-187, termed I-GSK-3s, 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 dysfunctional cytokine expression. First, COB-187 consists of a thiazolidine-2-thione ring that has a hydroxyl and phenyl group attached to one of the ring carbons. We suspect that these groups are key to imparting COB-187’s potency and selectivity. Thus, in the first aim we will determine the importance of the ring-appended phenyl and hydroxyl groups to COB-187’s inhibitory activity. The results of these studies will be incorporated into our ongoing work aimed at refining the chemical definition of I-GSK-3s. Second, aberrant cytokine expression in response to foreign- or self-antigens underlies a host of pathological conditions. Specifically, the dysfunctional induction of CXCL10 through mechanisms involving 2’3’ cyclic GMP-AMP (cGAMP) is key to multiple disorders and is an attractive therapeutic target. Several studies suggest the involvement of GSK-3 in this pathway. Thus, in the second aim we will probe the hypothesis that I- GSK-3s inhibit, via suppression of GSK-3 activity, cGAMP-induced CXCL10 production. 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 dysfunctional cytokine expression.
