4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Alzheimer-Disease

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

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC

Topics: Alzheimer Disease; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Humans; Molecular Structure; Neuroprotective Agents; Proteolysis; Structure-Activity Relationship

Currently, no treatments exist that are able to directly treat against Alzheimer's disease (AD), and we are facing an inevitable increase in the near future of the amount of patients who will suffer from AD. Most animal models of AD are limited by not being able to recapitulate the entire pathology of AD. Recently an AD model in zebrafish was established by using the protein phosphatase 2A inhibitor, okadaic acid (OKA). Administering OKA to zebrafish was able to recapitulate most of the neuropathology associated with AD. Therefore, providing a drug discovery model for AD that is also time and cost efficient. This study was designed to investigate the effects of GSK3β inhibition by 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8) on this newly developed AD model. Fish were divided into 4 groups and each group received a different treatment. The fish were divided into a control group, a group treated with 1 μM TDZD-8 only, a group treated with 1 μM TDZD-8 + 100 nM OKA, and a group treated with 100 nM OKA only. Administering the GSK3β inhibitor to zebrafish concomitantly with OKA proved to be protective. TDZD-8 treatment reduced the mortality rate, the ratio of active: inactive GSK3β, pTau (Ser199), and restored PP2A activity. This further corroborates the use of GSKβ inhibitors in the treatment against AD and bolsters the use of the OKA-induced AD-like zebrafish model for drug discovery.

Topics: Alzheimer Disease; Animals; Brain; Cognition; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Neurons; Okadaic Acid; tau Proteins; Thiadiazoles; Zebrafish

Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3β and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Central Nervous System Agents; Circular Dichroism; Drug Design; Drug Evaluation, Preclinical; Fluorescence Resonance Energy Transfer; Glycogen Synthase Kinase 3; Hep G2 Cells; Humans; Microscopy, Atomic Force; Molecular Targeted Therapy; Okadaic Acid; Phosphorylation; Protein Kinase Inhibitors; Rats; Structure-Activity Relationship; Swine; tau Proteins; Thiazolidinediones

Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Gene Expression Profiling; Glycogen Synthase Kinase 3; Humans; Kelch-Like ECH-Associated Protein 1; Lithium Chloride; Longevity; Mice; Microscopy, Confocal; Neurons; NF-E2-Related Factor 2; Oleanolic Acid; Peptide Fragments; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Thiadiazoles; Triazoles

Glycogen synthase kinase 3 beta (GSK-3beta) has a central role in Alzheimer's disease (AD). Selective inhibitors which avoid tau hyperphosphorylation may represent an effective therapeutical approach to the AD pharmacotherapy and other neurodegenerative disorders. Here, we describe the synthesis, biological evaluation, and SAR of the small heterocyclic thiadiazolidinones (TDZD) as the first non-ATP competitive inhibitor of GSK-3beta. Their synthesis is based on the reactivity of sulfenyl chlorides. In GSK-3beta assays, TDZD derivatives showed IC(50) values in the micromolar range, whereas in other protein kinases assays they were devoid of any inhibitory activity. SAR studies allowed the identification of the key structural features. Finally, a possible enzymatic binding mode is proposed.

Topics: Adenosine Triphosphate; Alzheimer Disease; Amino Acid Sequence; Animals; Binding, Competitive; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Molecular Sequence Data; Rabbits; Rats; Structure-Activity Relationship; Thiadiazoles