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. 1. Introduction Protein kinases regulate diverse cellular functions and thus are frequently exploited in drug discovery programmes [1]. They regulate signal transduction processes by phosphorylating serine, threonine and tyrosine residues in key proteins. The signalling pathways involved contribute to the pathology in many diseases [2, 3]. Glycogen synthase kinase 3 (GSK-3) was identified in the late 1970s and is a constitutively active, ubiquitous expressed serine/threonine kinase, which participates in a number of physiological processes ranging from glycogen metabolism to gene transcription [4]. Initially, the focus of pharmaceutical companies concerning GSK-3 was on diabetes mellitus, but since GSK-3 was linked to Alzheimer’s disease (AD), the focus has moved from diabetes to AD. GSK-3 has been linked to all primary abnormalities associated with AD. GSK-3 interacts with different components of the plaque producing amyloid system, participates in phosphorylating the microtubule binding protein tau that contributes to the formation of neurofibrillary tangles, and has an influence on presenilin and other AD-associated proteins [4–8]. Two related isoforms of GSK-3 are present in mammalians, GSK-3α and β, which share 98% homology in their catalytic domains and have similar biochemical properties [9]. The isoforms are similar in their catalytic domains, yet differ significantly in their N-terminal regions [10]. Alois Alzheimer’s first report of the neuropathological
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