Ohio University

Modulating the Activity of GSK-3 to Treat Multiple Pathologies

Overview

Glycogen synthase kinase-3 (GSK-3) is a protein kinase that has been implicated in a number of pathologies, including bipolar disorder, Alzheimer’s disease, schizophrenia, pathological inflammation, and diabetes. Identifying selective inhibitors for GSK-3 to aid in the treatment of these pathologies, however, is difficult due to the similarities among the catalytic domains of kinases. Research at Ohio University has led to the development and testing of novel compounds that are highly specific for GSK-3.  This group of small organic compounds, represented by the molecule known as I-187, inhibit both isozymes of GSK-3 (α and β) with IC50 values in the nanomolar range, and have a limited effect on other kinases. These data make compounds like I-187 attractive targets for further development and testing as potential treatments for GSK-3-mediated pathologies.

Existing GSK-3 Inhibitor results compared with newly discovered I-187

Above: An existing GSK-3 kinase inhibitor and I-187 were screened in 313 kinase assays, representing 404 unique kinases. Each cell in the above tables represents the result of a particular kinase assay. Red cells indicate significant inhibition; while cells modest inhibition; and blue cells little to no inhibition. The existing GSK-3 inhibitor hits a multitude of off-target kinases, while I-187 is very specific (two red cells are GSK-3α/β) demonstrating a substantial improvement in specificity. 

 

OU Ref: 14006  View PDF

Issued Patents:

US Patent 10,023,567, “Imidazole and Thiazole Compositions for Modifying Biological Signaling.” Issued July 17, 2018.
US Patent 10,407,420, “Imidazole and Thiazole Compositions for Modifying Biological Signaling.”  Issued September 10, 2019.

Published Applications

US20200017489A1 “Imidazole and Thiazole Compositions for Modifying Biological Signaling.” Published January 16, 2020

 

About the Inventors

Dr. Douglas Goetz, Ph.D., Professor of Chemistry & Bimolecular Engineering
Dr. Kelly McCall, Ph.D., Associate Professor of Specialty Medicine at Ohio University Heritage College of Osteopathic Medicine
Dr. Stephen C. Bergmeier, PhD, Professor and Chair, Chemistry & Biochemistry
Dr. Frank Schwartz, M.D. FACE, is the J O Watson Chair for Diabetes Research at Ohio University