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Glycogen Synthase Kinase-3 (GSK-3): A Kinase with Exceptional Therapeutic Potential
Glycogen Synthase Kinase-3 (GSK-3): A Kinase with Exceptional Therapeutic Potential John W. Benbow, Christopher J. Helal, Daniel W. Kung and Travis T. Wager Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc, Eastern Point Road, Groton, Connecticut, USA 06340 Contents 1. Introduction 2. Biology of GSK-3 2.1. Glycogen synthase kinase-3 features and functions 2.2. Lithium as proof of concept 3. Small molecule inhibitors of GSK-3 3.1. Natural product derived GSK-3 inhibitors 3.2. Maleimides 3.3. Other chemical series 4. Conclusion References
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1. INTRODUCTION 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 IressaTM, 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 ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 40 ISSN: 0065-7743 DOI 10.1016/S0065-7743(05)40009-3
r 2005 Elsevier Inc. All rights reserved
135 136 136 137 138 138 139 141 145 145
1. INTRODUCTION 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 IressaTM, 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 ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 40 ISSN: 0065-7743 DOI 10.1016/S0065-7743(05)40009-3
r 2005 Elsevier Inc. All rights reserved