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

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.

Glycogen Synthase Kinase 3β (GSK3β) Modulates Antiviral Activity of Zinc-finger Antiviral Protein (ZAP)

“…Other GSK3␤ inhibitors are being tested for the treatment of Alzheimer disease (31)(32)(33), type 2 diabetes (32,34), and osteoporosis (31). Our results showing that inhibition of GSK3␤ compromises the antiviral activity of ZAP suggest that precautions should be taken in the clinical use of GSK3␤ inhibitors.…”

Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor

“…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]. This inhibitor is approximately equipotent against both isoforms of GSK-3 (α/β).…”

Mice with beta cell overexpression of glycogen synthase kinase-3β have reduced beta cell mass and proliferation

“…An increasing body of literature has demonstrated the diverse functions of GSK3 in the regulation of cellular structure, mobility, proliferation, apoptosis and metabolism [9,10]. Originally identified as a modulator of glycogen metabolism [11], GSK3 shows enhanced activity in insulin-resistant states [12,13] and has been proposed as a potential therapeutic target for the treatment of diabetes [14][15][16]. GSK3 expression and activity were shown to be increased in skeletal muscle samples from patients with type 2 diabetes [13].…”