Back to Search
Start Over
Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3.
- Source :
- American Journal of Physiology: Cell Physiology; Dec2019, Vol. 317 Issue 6, pC1289-C1303, 15p, 2 Color Photographs, 1 Diagram, 2 Charts, 7 Graphs
- Publication Year :
- 2019
-
Abstract
- Glycogen synthase kinase-3 (GSK-3) is a multitasking protein kinase that regulates numerous critical cellular functions. Not surprisingly, elevated GSK-3 activity has been implicated in a host of diseases including pathological inflammation, diabetes, cancer, arthritis, asthma, bipolar disorder, and Alzheimer’s. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Finding a potent inhibitor of GSK-3 that can selectively target this kinase, among over 500 protein kinases in the human genome, is a significant challenge. Thus there remains a critical need for the identification of selective inhibitors of GSK-3. In this work, we introduce a novel small organic compound, namely COB-187, which exhibits potent and highly selective inhibition of GSK-3. Specifically, this study 1) utilized a molecular screen of 414 kinase assays, representing 404 unique kinases, to reveal that COB-187 is a highly potent and selective inhibitor of GSK-3; 2) utilized a cellular assay to reveal that COB-187 decreases the phosphorylation of canonical GSK-3 substrates indicating that COB-187 inhibits cellular GSK-3 activity; and 3) reveals that a close isomer of COB-187 is also a selective and potent inhibitor of GSK-3. Taken together, these results demonstrate that we have discovered a region of chemical design space that contains novel GSK-3 inhibitors. These inhibitors will help to elucidate the intricate function of GSK-3 and can serve as a starting point for the development of potential therapeutics for diseases that involve aberrant GSK-3 activity. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03636143
- Volume :
- 317
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- American Journal of Physiology: Cell Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 159044419
- Full Text :
- https://doi.org/10.1152/ajpcell.00061.2019