Research ArticlePharmacology

A unique type of GSK-3 inhibitor brings new opportunities to the clinic

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Sci. Signal.  15 Nov 2016:
Vol. 9, Issue 454, pp. ra110
DOI: 10.1126/scisignal.aah7102

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GSK-3 makes its own inhibitor

One of the main challenges in developing kinase inhibitors has been achieving specificity. Licht-Murava et al. discovered a substrate peptide derivative, L807, that the kinase GSK-3 converted into an inhibitor within the catalytic site of the enzyme. This peptide was highly selective for GSK-3 when tested against a panel of 139 kinases, and a membrane-permeable form of it inhibited GSK-3 activity in cells and animals and, more importantly, improved cellular symptoms, cognitive function, and social behaviors in a mouse model of Alzheimer’s disease. Thus, this new mechanism of inhibition may finally enable effective and selective GSK-3 inhibitors to reach the clinic.

Abstract

Development of protein kinase inhibitors is a focus of many drug discovery programs. A major problem, however, is the limited specificity of the commonly used adenosine triphosphate–competitive inhibitors and the weak inhibition of the more selective substrate-competitive inhibitors. Glycogen synthase kinase–3 (GSK-3) is a promising drug target for treating neurodegenerative disorders, including Alzheimer’s disease (AD), but most GSK-3 inhibitors have not reached the clinic. We describe a new type of GSK-3 inhibitor, L807mts, that acts through a substrate-to-inhibitor conversion mechanism that occurs within the catalytic site of the enzyme. We determined that L807mts was a potent and highly selective GSK-3 inhibitor with reasonable pharmacological and safety properties when tested in rodents. Treatment with L807mts enhanced the clearance of β-amyloid loads, reduced inflammation, enhanced autophagic flux, and improved cognitive and social skills in the 5XFAD AD mouse model. This new modality of GSK-3 inhibition may be therapeutic in patients with AD or other central nervous system disorders associated with dysregulated GSK-3.

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