Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects
Florence F Wagner, Joshua A Bishop1, Jennifer P Gale
1Chemical Neurobiology Laboratory, Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02215, United States.
ACS Chemical Biology
|April 30, 2016
Summary
Researchers discovered novel, highly selective glycogen synthase kinase 3 (GSK3) inhibitors, BRD1652 and BRD0209. These compounds show promise for treating mood disorders by targeting GSK3 kinases involved in Wnt signaling pathways.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Lithium, a mood stabilizer for bipolar disorder, targets glycogen synthase kinase 3 (GSK3).
- GSK3, comprising GSK3α and GSK3β, is crucial in the Wnt pathway and a therapeutic target for various diseases.
- Existing GSK3 inhibitors often lack selectivity or suitable properties for research.
Purpose of the Study:
- To discover novel GSK3 inhibitors with high kinome-wide selectivity.
- To develop potent chemical probes for studying GSK3 function in disease models.
Main Methods:
- High-throughput screening of GSK3β inhibitors, excluding known chemotypes.
- Structure-based design leveraging a tridentate interaction with GSK3.
- In vivo efficacy testing in a dopaminergic signaling model for mood disorders.
Main Results:
- Discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with selective GSK3 inhibition.
- Development of potent GSK3 inhibitors BRD1652 and BRD0209.
- Demonstration of in vivo efficacy of these inhibitors in a mood disorder model.
Conclusions:
- Novel, highly selective GSK3 inhibitors (BRD1652, BRD0209) were developed.
- These inhibitors offer a valuable tool for dissecting GSK3 roles in signaling pathways and diseases.
- The findings advance therapeutic strategies for mood disorders and other conditions involving GSK3.
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