Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer’s Disease

Abstract

Glycogen synthase Kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3β, serving as a central switch in the signalling pathways. Dysregulation of GSK-3β kinase has been reported in cancer, diabetes, Alzheimer's disease, schizophrenia, bipolar disorder, inflammation, and Huntington's disease. Thus, GSK-3β is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer's disease, an age-related neurodegenerative brain disorder. GSK-3β activation increases amyloid-beta (Aβ) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3β are explored, and different existing classes of GSK-3β inhibitors are explained in this review. Non-ATP competitive inhibitors, such as allosteric inhibitors, can reduce the side effects compared to ATP-competitive inhibitors. Whereas ATP-competitive inhibitors produces disarrangement of the cytoskeleton, neurofibrillary tangles formation, and leads to the death of neurons, etc. This could be because they are binding to a site separate from ATP. Owing to their interaction in particular and special binding sites, allosteric ligands interact with substrates more selectively, which will be beneficial in resolving drug-induced resistance and also helpful in reducing side effects. Hence, in this review, we focussed on the allosteric GSK-3β inhibitors and discussed their futuristic opportunities as anti-Alzheimer’s drug.

Influence of β‐catenin signaling on neurogenesis in neuropsychiatric disorders: Anxiety and depression

“…Regarding anxiolytics, the benzodiazepine (BDZ) class is one of the most effective anxiolytics. Of note, benzothiazepines like diazepam are GSK‐3β allosteric inhibitors that influence β‐catenin activity (Shri et al, 2023). The JM‐20, a BDZ derivative, protects against neuronal damage and counteracts cognitive and memory impairments by normalizing phosphorylated GSK‐3β (Wong‐Guerra et al, 2021).…”

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

“…Specific inhibition of GSK signaling attenuates APP cleavage by BACE1, ameliorating memory deficits in animal models [ 18 , 19 , 20 ]. GSK-3β is a key regulator of processes that underlie the development of Alzheimer’s disease; therefore, the search for its inhibitors has been widely studied [ 21 , 22 , 23 , 24 , 25 , 26 ]. These efforts led to the discovery of various selective and potent inhibitors, among which several exhibited activity in animal models of AD [ 27 ]; however, only one has reached clinical trials in humans to date.…”