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Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2019 Dec 01; Vol. 317 (6), pp. C1289-C1303. Date of Electronic Publication: 2019 Sep 25. - 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.
- Subjects :
- Animals
Biphenyl Compounds chemical synthesis
Drug Design
Enzyme Assays
Gene Expression
Glycogen Synthase Kinase 3 beta genetics
Glycogen Synthase Kinase 3 beta metabolism
HEK293 Cells
High-Throughput Screening Assays
Humans
Mice
Phosphorylation
Protein Kinase Inhibitors chemical synthesis
Protein Kinases genetics
RAW 264.7 Cells
Structure-Activity Relationship
Substrate Specificity
THP-1 Cells
Tetradecanoylphorbol Acetate pharmacology
Thiadiazoles chemistry
Thiadiazoles pharmacology
Biphenyl Compounds pharmacology
Glycogen Synthase Kinase 3 beta antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1563
- Volume :
- 317
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 31553649
- Full Text :
- https://doi.org/10.1152/ajpcell.00061.2019