Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Abstract

The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreased β-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidate in vivo studies and pre-/clinical trials.

PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome

“…Our results suggest that activation of GSK3 may be a promising way to enhance the serum adiponectin level and to combat metabolic syndrome. On the other hand, several GSK3 inhibitors are currently being developed and tested for the treatment of Alzheimer's disease (59,60). In view of the present observations, those substances may share with lithium (50) the negative influence on serum adiponectin levels, potentially leading to a negative cardiovascular safety profile (55,61).…”

“…Glucose (2 g/kg body weight) was injected intraperitoneally (i.p.). The blood glucose concentration was determined in a blood drop from the tail vein before as well as 15,30,45,60,90, and 120 min after the injection with a glucometer.…”

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…Whereas, the amino and carbonyl functionalities of the cyclic amide group may act as H-bond donor and acceptor, respectively, thus forming H-bond interactions with the backbone of the GSK-3β hinge region. This cyclic amide function, present in numerous ATP-competitive inhibitors of GSK-3β, that is indirubins, maleimides and paullones, among others, is a signature for kinase binding, providing a specific H-bond network [54].…”

Role of Presenilin-1 in Modulating Glycogen Synthase Kinase 3 β Expression in the Pathogenesis of Alzheimer’s Disease

“…The phosphorylation of PS-1, due to GSK3β at Ser353 and Ser357 of the hydrophilic loop domain affects the formation or stability of this PS-1/cadherin/β-catenin complex, reducing PS-1 binding to cadherin and downregulating its cell surface expression. Moreover, reduction of the PS-1/cadherin/β-catenin complex formation leads to an impaired activation of another cell signaling pathway, the PI3K/Akt (phosphatidylinositol 3-kinase/protein kinase identified in the Akt virus, also known as protein kinase B) pathway (46,58,50).…”

“…GSK3β is also essential for life and there is grave concern regarding its implication in disallowing host cells to function normally (57). Thus the use of these inhibitors must strike a balance between the different pathways, which can be achieved via a moderate inhibition in combination with excellent pharmacokinetics and excellent BBB permeation (58).…”