Glycogen synthase kinase-3 (GSK-3): A kinase with exceptional therapeutic potential

The human genome analysis has shown that there are more than 500 kinases that, along with phosphatases, play an essential role in the regulation of enzymes and structural proteins. As our understanding of cellular signaling processes increases, kinases have emerged as attractive targets for disease therapy [1]. Kinase activity is regulated through a complex series of priming events leading to phosphorylation of specific protein substrates that generally activate downstream targets. Common approaches towards kinase regulation focus on small molecule inhibitors that effectively compete for the endogenous substrate adenosine triphosphate, ATP. The ATP binding site is highly conserved amongst kinases and particularly high homology exists within kinase sub-families, such that isoform selectivity is a major obstacle to developing a successful small molecule therapy. Current small-molecule kinase inhibitors capitalize on various structural attributes to achieve the desired affect. The Abelson tyrosine kinase (Abl) inhibitor GleevecTM buries the key kinase activation loop upon binding, thereby providing the necessary selectivity profile over the related Src kinases [2]. Both Iressa™, an inhibitor of the epidermal growth factor receptor, and a P38 MAPK inhibitor for treating inflammation have been reported to achieve selectivity through interactions at the ATP-binding site [3,4]. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that is ubiquitously expressed in mammalian tissues. As opposed to other kinases, GSK-3 is unusual in that it is constitutively active and it negatively regulates its downstream targets. GSK-3 has been implicated in a wide variety of disease states including obesity and type 2 diabetes mellitus [5], neurological disorders (e.g., Alzheimer's disease, bipolar disorder, neuronal cell death and stroke, depression) [6-8], inflammation [9,10], cardio-protection [11,12], cancer [13], skeletal muscle atrophy [14] and myotube hypertrophy [15], hair loss [16] and decreased sperm motility [17]. Comprehensive surveys on the chemistry [18,19], biology [19-28] and pharmacology [5-7,29-34] of GSK-3 inhibition have appeared. © 2005 Elsevier Inc. All rights reserved.