4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Neoplasms

Glycogen synthase kinase-3β (GSK-3β) is a conserved serine/threonine kinase that participates in the transmission of multiple signaling pathways and plays an important role in the occurrence and development of human diseases, such as metabolic diseases, neurological diseases and cancer, making it to be a potential and promising drug target. To date, copious GSK-3β inhibitors have been synthesized, but only few have entered clinical trials. Most of them exerts poor selectivity, concomitant off-target effects and side effects. This review summarizes the structural characteristics, biological functions and relationship with diseases of GSK-3β, as well as the selectivity profile and therapeutic potential of different categories of GSK-3β inhibitors. Strategies for increasing selectivity and reducing adverse effects are proposed for the future design of GSK-3β inhibitors.

Topics: Glycogen Synthase Kinase 3 beta; Humans; Neoplasms

Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and β-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation. In addition, a detailed description of the small molecule inhibitors of GSK-3 with different mode of action discovered or specifically developed for GSK-3 has been presented. Furthermore, some clues for the future optimization of these promising molecules to develop specific drugs inhibiting GSK-3, for the treatment of associated disease conditions have also been discussed.

Topics: Alzheimer Disease; Animals; Bipolar Disorder; Clinical Trials as Topic; Diabetes Mellitus; Drug Discovery; Glycogen Synthase Kinase 3; Humans; Models, Molecular; Neoplasms; Patents as Topic; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction

Three closely related forms of glycogen synthase kinase 3 (GSK-3alpha, GSK-3beta and GSK-3beta2) have a major role in Wnt and Hedgehog signaling pathways and regulate the cell-division cycle, stem-cell renewal and differentiation, apoptosis, circadian rhythm, transcription and insulin action. A large body of evidence supports speculation that pharmacological inhibitors of GSK-3 could be used to treat several diseases, including Alzheimer's disease and other neurodegenerative diseases, bipolar affective disorder, diabetes, and diseases caused by unicellular parasites that express GSK-3 homologues. The toxicity, associated side-effects and concerns regarding the absorption, distribution, metabolism and excretion of these inhibitors affect their clinical potential. More than 30 inhibitors of GSK-3 have been identified. Seven of these have been co-crystallized with GSK-3beta and all localize within the ATP-binding pocket of the enzyme. GSK-3, as part of a multi-protein complex that contains proteins such as axin, presenilin and beta-catenin, contains many additional target sites for specific modulation of its activity.

Topics: Animals; Cell Differentiation; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Humans; Neoplasms; Nervous System Diseases; Parasitic Diseases; Signal Transduction; Stem Cells; Structure-Activity Relationship