# Novel Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Therapeutic Agents

> **NIH NIH R15** · OHIO UNIVERSITY ATHENS · 2021 · $453,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10203167
- **Project number:** 2R15GM110602-02
- **Recipient organization:** OHIO UNIVERSITY ATHENS
- **Principal Investigator:** DOUGLAS J GOETZ
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $453,000
- **Award type:** 2
- **Project period:** 2016-09-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10203167

## Citation

> US National Institutes of Health, RePORTER application 10203167, Novel Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Therapeutic Agents (2R15GM110602-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10203167. Licensed CC0.

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