Since the mid-1990s there has been a near exponential rise in the level of glycogen synthase kinase-3 (GSK-3) related research. Consequently the therapeutic potential of GSK-3 inhibitors has become a major area of pharmaceutical interest. A recent report produced by LeadDiscovery analysts under the editorial guidance of field-leader, Dr Hagit Eldar-Finkelman, offers a state of the art overview of GSK-3 analyzing the therapeutic role of inhibitors of this enzyme. The report concludes that there is particularly strong evidence to support the development of GSK-3 inhibitors as 1) antihyperglycemic, insulin sensitizing and insulinotropin agents for use in diabetics; 2) inhibitors of neuronal apoptosis and neurological decline in stroke patients; 3) blockers of the accumulation and toxicity of Aß/tau in Alzheimer's disease. In addition, the GSK-3 inhibitory activity of diverse mood stabilizers suggests that bipolar disorder represents a further indication for this therapeutic class.

The support for targeting GSK-3 as a treatment of diabetes arises from the ability of this enzyme to negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. Glycogen synthase appears to be the rate-limiting step for glycogen synthesis, at least in the liver, and it has been shown that GSK-3 inhibition increases liver glycogen synthesis. This improved glucose handling in Zucker diabetic fatty rats, lowering fasting hyperglycemia. Likewise GSK-3 inhibitors stimulated glucose incorporation into glycogen in cultured human skeletal muscle cells.

GSK-3 has also been shown to phosphorylate IRS-1, which in turn attenuates insulin signaling however a limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. Researchers at Chiron, who have developed the field-leading GSK-3 inhibitors CT98014 and CHIR98023 researchers have recently demonstrated that their molecules activate glycogen synthase in cultured CHO cells transfected with the insulin receptor; in primary hepatocytes; and in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. Of note, these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, these results represent a major advance in the development of GSK-3 inhibitors for the treatment of the insulin resistance of type 2 diabetes. Not only do these results offer further convincing evidence relating to the concept of developing GSK-3 inhibitors for this condition but they also strongly support the further development of Chiron’s therapeutic candidates.

Readers involved in the development of this therapeutic area should be aware of the “Kinase Enterprise Library” recently highlighted by LeadDiscovery. This library represents a highly targeted collection of molecules expanded from a diverse collection of kinase inhibitor templates. The library is ready for screening for inhibitors of GSK-3.

Entry date March, 2003

Adapted from Ring et al, Diabetes 2003 Mar;52(3):588-95.

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