Cited by 154Wnt/β-catenin signaling in development and cancerDiabetes Treatment and ManagementMetabolism, Diabetes, and Cancer

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Discovery and Development of GSK3 Inhibitors for the Treatment of Type 2 Diabetes

Wagman, Allan, Johnson, Kirk, Bussiere, Dirksen·2004·Current Pharmaceutical Design

DOI 10.2174/1381612043452668

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Abstract

Originally identified as a modulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now understood to play an important regulatory role in a variety of pathways including initiation of protein synthesis, cell proliferation, cell differentiation, apoptosis, and is essential for embryonic development as a component of the Wnt signaling cascade. GSK3 can be considered as a target for both metabolic and neurological disorders. GSK3's association with neuronal apoptosis and hyper-phosphorylation of tau make this kinase an attractive therapeutic target for neurodegenerative conditions such as head trauma, stroke and Alzheimer's disease. While noting GSK3's many associated functions, this review will focus on GSK3 as a central negative regulator in the insulin signaling pathway, its role in insulin resistance, and the utility of GSK3 inhibitors for intervention and control of metabolic diseases including type 2 diabetes. Recent crystal structures, including the active (phosphorylated Tyr-216) form of GSK3beta, provide a wealth of structural information and greater understanding of GSK3's unique regulation and substrate specificity. Many potent and selective small molecule inhibitors of GSK3 have now been identified, and used in vitro to modulate glycogen metabolism and gene transcription, increase glycogen synthase activity and enhance insulin-stimulated glucose transport. The pharmacology of potent and selective GSK3 inhibitors (CT 99021 and CT 20026) is described in a number of in vitro and in vivo models following acute or chronic exposure. The efficacy of clinical candidates in diabetic primates and the implications for clinical development are discussed. The profile of activity is consistent with a unique form of insulin sensitization which is well suited for indications such as metabolic syndrome X and type 2 diabetes.

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Authors: Wagman, A., Johnson, K., & Bussiere, D.
ORCID: Johnson, Kirk
Bussiere, Dirksen
Venue: Current Pharmaceutical Design
Publisher: Bentham Science Publishers Ltd.
Published: 2004-04-01
Volume: 10
Issue: 10
Pages: 1105-1137
ISSN: 1381-6128 (ISSN-L)
DOI: 10.2174/1381612043452668
OpenAlex: W2146895097
Cited by: 153
References: 0
Citations by year: 2026: 2 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 5 · 2014: 6 · 2013: 8 · 2012: 5
FWCI: 4.62
Type: journal article
Language: en
Open access: closed
Locations: Current Pharmaceutical Design (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: glycogen synthase kinase-3, GSK-3 inhibitors, type 2 diabetes, insulin resistance, insulin signaling, insulin sensitization, glycogen metabolism, Wnt signaling, tau hyperphosphorylation, metabolic syndrome, small-molecule kinase inhibitors, clinical development
MeSH terms: Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Enzyme Inhibitors, Humans, Hypoglycemic Agents, Models, Molecular, Substrate Specificity, Drug Design, Molecular Structure, Glycogen Synthase Kinase 3

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Discovery and Development of GSK3 Inhibitors for the Treatment of Type 2 Diabetes

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