Glycogen synthase kinase 3 beta (GSK-3β) is an attractive target for the treatment of psychiatric disorders and neurodegenerative diseases. Many GSK-3β inhibitors have been developed for the treatment of different central nervous system disorders. But, for an effective therapy, high IC50 values should be avoided and ATP-competition should be reduced during enzyme-compound binding. Studies suggested that ATP non-competitive GSK-3 inhibitors such covalent inhibitors and allosteric modulators are emerging as a promising approach with better efficacy and safety.
Despite of many GSK-3β inhibitors in clinical studies, many challenges still remains. In a clinical study, certain adverse events caused by off-target activity of GSK-3β inhibitors were determined after the screening of compounds that bind to the ATP-competitive binding site conserved across a broad range of kinases. Thus, there is an urgent need of development of GSK-3β inhibitors that can selectively target individual pathways and differentiate between the non-phosphorylated and phosphorylated GSK-3β.
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Company like AMO Pharma Ltd. is in the process of developing AMO-02 as a small molecule which acts as a GSK-3β inhibitor for the treatment of congenital myotonic dystrophy.
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