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

Wagman, Allan; Johnson, Kirk; Bussiere, Dirksen

doi:10.2174/1381612043452668

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

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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The concentration of GSK-3 inhibitor causing half-maximal glycogen synthase stimulation (EC50) in CHO-IR cells was 66 nmol/l.
“The concentration of GSK-3 inhibitor causing half-maximal glycogen synthase stimulation (EC 50 ) in CHO-IR cells was 66 nmol/l [35], which is similar to the EC 50 observed in soleus muscles in this study (data not shown).”
From Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor (2005) · cites this paper as [35]
CHIR-637 is an ATP-competitive inhibitor of GSK-3β with an IC50 of 4 nmol/l in a cell-free binding assay.
“CHIR-637, a low-molecular weight (531 Da) small molecule, is an ATP-competitive inhibitor of GSK-3β giving an IC 50 of 4 nmol/l in a cell-free binding assay [35].”
From Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor (2005) · cites this paper as [35]
CHIR-637 is approximately equipotent against both isoforms of GSK-3 (α/β).
“This inhibitor is approximately equipotent against both isoforms of GSK-3 (α/β).”
From Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor (2005) · cites this paper as [35]
CHIR-637 exhibits >2,500-fold selectivity against a panel of 16 other protein kinases, including cdc2 and erk2.
“Like other GSK-3 inhibitors in this class, it exhibits >2,500-fold selectivity against a panel of 16 other protein kinases, including cdc2 and erk2, which are the closest homologues of GSK-3.”
From Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor (2005) · cites this paper as [35]

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“Reagents Sources of chemicals were TDZD-8 (Calbiochem), sodium butyrate, valproic acid, trichostatin A (TSA), anacardic acid, 59azacytidine, LiCl (Sigma), pargyline (Alexis), tubacin (a gift from Dr. Mazitschek) and CT99021 (University of Dundee, UK).”
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“Acute administration of these substituted aminopyrimidine GSK-3 inhibitors causes a significant lowering of blood glucose, dramatically improves whole body glucose tolerance and insulin sensitivity, and enhances insulin-stimulated skeletal muscle glucose transport activity in a variety of mouse and rat models of obesi…”
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BackgroundMethodInfluential
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Background
Theoretical Studies on the Selectivity Mechanisms of Glycogen Synthase Kinase 3β (GSK3β) with Pyrazine ATP-competitive Inhibitors by 3DQSAR, Molecular Docking, Molecular Dynamics Simulation and Free Energy Calculations
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“GSK-3b can be used as a target for drugs against a number of diseases; evidence has been obtained for the possible therapeutic role of GSK-3b inhibitors in type 2 diabetes (4), Alzheimer's disease (5), bipolar disorder (6), and some others (7).”
Background
Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer
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“The data further suggest that the mechanism by which CHIR99021 inhibits growth is via its ability to inhibit GSK3α/β although, despite it being the most selective ATP-competitive GSK3 inhibitor available [32], we cannot exclude the possibility that at least some aspects of its action are the result of effects on kinas…”
Background
Monte Carlo method based QSAR modeling of maleimide derivatives as glycogen synthase kinase-3β inhibitors
Živković, J. V., Trutić, N., Veselinović, J. B., Nikolić, G. M., & Veselinović, A. M. (2015) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2015.07.004 · Cited by 25 · see citing works
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Background
Small‐molecule inhibition of inflammatory β ‐cell death
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Role of Glycogen Synthase Kinase-3 in the Etiology of Type 2 Diabetes Mellitus: A Review
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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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