GSK-3 inhibitors for the Treatment of Insulin Resistance-Related Diseases

Invention Novel inhibitors of GSK-3 were identified. These inhibitors represent substrate competitors that interact specifically with the GSK-3 substrate binding site. GSK-3 modulates insulin action by controlling the activity of two other proteins in the insulin-signaling pathway, and its activity is elevated in insulin resistant and type II diabetic tissues. Reducing GSK-3 activity should, therefore, alleviate the deleterious effect and restore insulin responses including glucose uptake and glycogen synthesis. Since GSK-3 has been discovered to be a promising new drug target, these inhibitors are expected to be useful in combating diseases with elevated GSK-3 activity such as Type II diabetes. Additional applications include bipolar disorder and Alzheimer's disease.
The Need Diabetes type II is a primary target indication for GSK-3 inhibitor therapy. It represents a great unmet medical need since current therapy to overcome insulin resistance remains inadequate for many patients having limited efficacy, limited tolerability and significant mechanism-based side effects. Of particular concern is the tendency for most treatments to enhance weight gain. Several current approaches are also associated with episodes of hypoglycemia, and few of the available therapies adequately address underlying defects such as obesity and/or insulin resistance. New approaches to diabetes type II, the most common chronic disease in the western world, are desperately needed.
Potential Applications Novel treatment for:

Diabetes type II Neurological diseases including:
- Alzheimer’s disease - Bipolar disorders - Huntington disease - Parkinson's disease
Advantages Novel mechanism of action inhibiting a key therapeutic drug target GSK-3. High specificity - binding to the GSK-3 enzyme substrate binding site, as compared to nonspecific ATP analog protein kinase inhibitors. Widely applicable to different indications including Type II diabetes, bipolar disease and Alzheimer’s disease. Rational drug design, for substrate competitive GSK-3 inhibitors, based on the specific binding / recognition motif.
Stage A peptide inhibitor of GSK-3 substrate recognition site (L-830-mts):
The short phosphorylated peptide (L803-mts) was selected as the best peptide inhibitor of GSK-3:
- L803-mts acts as insulin mimetic in an animal model for diabetes (obese mice). In vitro studies confirmed that L803-mts provokes profound metabolic effects in liver and muscle. - In vivo, daily treatment with L803-mts attenuates insulin resistance and improves glucose tolerance in diabetic mice. - Toxicology studies indicate no adverse effects at high doses.

GS series of small molecules:

Based on the GSK-3 substrate 3-D structure, a 'general' template for an inhibitor that interacts with the GSK-3 substrate binding site was designed. Several families of small molecules were synthesized and the lead compound GSC-7 selected as the lead:

GSC-7 reduces blood glucose levels in diabetic mouse models, and improves glucose tolerance. GSC-7 reduces fat mass and decreases fat deposits in the liver. Blood chemistry analyses point toward reduction of cholesterol and triglycerides lipid content. Toxicology studies indicate no adverse effects at high doses. GSC-7 is reasonably stable in mouse, rat and human serum. Depression

The impact of the GSK-3 peptide inhibitor L803-mts on depressive behavior was demonstrated using a widely accepted preclinical animal model of anti-depressive drug activity, the forced swimming test:

L803-mts administered ICV produced a rapid antidepressant-like effect in mouse forced swimming test: Inhibition of GSK-3 led to accumulation of -catenin in the mouse hippocampus, that has been recently implicated as an important modulator in brain development and neural network signaling. L803-mts administered ICV prevented depressive activity induced by mild traumatic brain injury.
References Eldar-Finkelman H, Ilouz R. (2003) Challenges and opportunities with glycogen synthase kinase-3 inhibitors for insulin resistance and Type 2 diabetes treatment. Expert Opin Investig Drugs. 12: 1511-9 Plotkin B, Kaidanovich O, Talior I, Eldar-Finkelman H. (2003) Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. J Pharmacol Exp Ther. 305: 974-80 Liberman Z. and Eldar-Finkelman H. (2005) Serine332 Phosphorylation of Insulin Receptor Substrate-1 by Glycogen Synthase Kinase-3 Attenuates Insulin Signaling. J. Biol. Chem. 280(6):4422-8 Kaidanovich-Beilien, O. and Eldar-Finkelman, H. (2006) Long-Term Treatment with Novel Glycogen Synthase Kinase-3 Inhibitor Improves Glucose Homeostasis in Ob/Ob Mice. Molecular Characterization In Liver And Muscle. J. Pharmacol. Exp. Ther. 316(1):17-24
Patent Issued: US; pending
Tech Transfer Officer Dr. Tamar Raz Office: +972-3-6406580 Fax: +972-3-6406675 Mail: [email protected]

Inventor(s): Hagit Eldar-Finkelman

Type of Offer: Licensing



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