GSK3 Inhibitors in the Therapeutic Development of Diabetes, Cancer and Neurodegeneration: Past, Present and Future

Abstract

GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus). Additionally, GSK3 stabilizes the components of beta-catenin complex, hence promotes oncogenesis. Phosphorylation of GSK3 by Akt and some other kinases also favours the carcinogenesis. However, in some cases GSK3 has tumor supressing character. GSK3 has been found to have a prominent role in the formation of amyloid plaques and neurofibrillary tangles (abnormal protein accumulations) which are the main suspects of Alzheimer's disease (AD). GSK3 inhibitors have been reported to have amyloidbeta disaggregation property and have been found to promote the adult hippocampal neurogenesis in vivo as well as in vitro. This manuscript thoroughly reviews the involvement of GSK3 in diabetes, cancer and ND. Furthermore, development of GSK3 inhibitors as antidiabetes, anticancer and antineurodegenerative agents focusing mainly on lead optimization has been discussed.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…GSK-3 participates in at least some pathophenotypes found in the NRF2 diseasome such as diabetes and neurodegeneration (Beurel et al, 2015;Maqbool and Hoda, 2017). A broad spectrum of GSK-3 inhibitors has been discovered from natural and synthetic origins (Khan et al, 2017), but probably the best evidence for repurposing a GSK-3 inhibitor to increase NRF2 activity stems from the clinical use of lithium as mood stabilizer (Chiu et al, 2013).…”

Glycogen synthase kinase 3β in tumorigenesis and oncotherapy (Review)

“…GSK 3β has been revealed to play a critical role in the regulation of a variety of cellular functions, including cell proliferation, differentiation, motility, apoptosis and the cell cycle ( 1 , 2 , 10 ). In addition, GSK3 inhibitors may be appropriate for the treatment of certain diseases, including diabetes, bipolar disorder, inflammation and certain types of cancer ( 91 ). Inhibitors of GSK 3β are categorized as GSK 3β-selective or non-selective and ATP-competitive or non-ATP-competitive ( 92 – 121 ).…”

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“…After complete depletion of the substituted benzaldehyde (VII), the mixture was cooled and the precipitate was filtered and washed with ethanol / water (1:5). 3-OCH 3 , 4-OH SP 3 4-OH SP 4 2-Cl SP 5 4-Cl SP 6 4-NO 2 SP 7 4-OH SP 8 3-Cl SP 9 3,4,5-tri (CH 3 )…”

“…Unique activities revealed that GSK-3β a competitive target for the treatment of various human diseases such as type -2 diabetes, 7 Alzheimer's disease (AD), 8 CNS disorders like manic depressive disorder and neurodegenerative diseases, 9 and chronic inflammatory disorders 10 . The search for GSK-3β inhibitors became a very active research trend for academic centers and pharmaceutical industry.…”

“…Glucose Diffusion Inhibitory Test: The results of the glucose diffusion inhibitory test are given in Table 2. All tested compound showed significant inhibitory activity with SP 9 showing maximum inhibition to the diffusion of glucose and SP 7 showing least inhibition to the diffusion of glucose. The data represented as mean ± SEM (n = 3)…”