Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases.
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Abstract | Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3β activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects associated with strong GSK-3β inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3β may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3β inhibition exhibits therapeutic effects. |
Year of Publication | 2017
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Journal | J Med Chem
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Volume | 60
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Issue | 12
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Pages | 4983-5001
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Date Published | 2017 Jun 22
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ISSN | 1520-4804
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DOI | 10.1021/acs.jmedchem.7b00395
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PubMed ID | 28548834
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