Supplementary Table S8 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Benedito A. CarneiroLudimila CavalcanteDevalingam MahalingamAnwaar SaeedHoward SafranWen WeeAndrew L. CovelerSteven PowellBruno R. BastosElizabeth J. DavisVaibhav SahaiWilliam MikrutJames LongstrethSheri SmithTaylor WeisskittelHu LiBrittany A. BordenR. Donald HarveySolmaz SahebjamAndrés CervantesAustin KoukolAndrew P. MazarNeeltje SteeghsRazelle KurzrockFrancis J. GilesPamela N. Münster
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<p>Tumor Types by Elraglusib Dose Level in Part 1</p>Keywords:
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Glycogen synthase kinase‐3 is involved in diverse functions including insulin signalling and development. In a number of substrates, phosphorylation by glycogen synthase kinase‐3 is known to require prior phosphorylation at a Ser in the +4 position relative to its own phosphorylation site. Here we have used synthetic peptides derived from a putative glycogen synthase kinase‐3 site in the Drosophila translation initiation factor eIF2Bϵ to investigate the efficacy of residues other than Ser(P) as priming residues for glycogen synthase kinase‐3β and its Drosophila homologue Shaggy. glycogen synthase kinase‐3β phosphorylated peptides with Ser(P) and Thr(P) in the priming position, but peptides with Tyr(P), Thr, Glu or Asp were not phosphorylated. The V max for the Thr(P) peptide was three times higher than that of the Ser(P) peptide. These data suggest that glycogen synthase kinase‐3 is unique among phosphate‐directed kinases. The priming site specificity of Shaggy is similar to that of mammalian glycogen synthase kinase‐3β. This unpredicted efficacy of Thr(P) in the priming position suggests that there may be other unidentified substrates for these kinases.
GSK3B
Phosphorylase kinase
Priming (agriculture)
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Multiple reports suggest that glycogen synthase kinase-3(GSK3)plays an important role in the pathogenesis of Alzheimer's disease(AD).The level and enzymatic activity of GSK3 is elevated in AD.Cell culture studies and animal model studies with both invertebrates and mammals find that over-activity of GSK3 causes hyper-phosphorylation of the tau protein,increased production of β-amyloid,learning and memory impairments,and associated neurodegeneration.GSK-3β inhibitors prevent tau hyper-phosphorylation in AD transgenic animals so they are of potential use in the prevention and treatment of AD.
Pathogenesis
GSK3B
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Glycogen synthase kinase 3 (GSK3), a constitutively acting multi‐functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, τ protein and β catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin‐mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti‐diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti‐diabetic but do not lead to up‐regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti‐diabetic therapeutic target. British Journal of Pharmacology (2009) doi:10.1111/j.1476‐5381.2008.00085.x
GSK3B
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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase, originally identified as a protein kinase by its ability to phosphorylate and inactivate glycogen synthase. It was found that the overexpression of GSK-3 is associated with some diseases, such as diabetes, Alzheimer disease and other neurodegenerative diseases. Some pharmacological inhibitors of GSK-3 have been demonstrated to mimic insulin signaling, adjust glycogen synthesis and glucose metabolism, and improve insulin resistance. So GSK-3 inhibitors are realized as a new approach of treating diabetes. This review summarizes current advances in research of GSK-3 inhibitors as a new therapeutic approach for diabetes.
GSK3B
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In these studies we expressed and characterized wild-type (WT) GSK-3 (glycogen synthase kinase-3) and its mutants, and examined their physiological effect on glycogen synthase activity. The GSK-3 mutants included mutation at serine-9 either to alanine (S9A) or glutamic acid (S9E) and an inactive mutant, K85,86MA. Expression of WT and the various mutants in a cell-free system indicated that S9A and S9E exhibit increased kinase activity as compared with WT. Subsequently, 293 cells were transiently transfected with WT GSK-3 and mutants. Cells expressing the S9A mutant exhibited higher kinase activity (2.6-fold of control cells) as compared with cells expressing WT and S9E (1.8- and 2.0-fold, respectively, of control cells). Combined, these results suggest serine-9 as a key regulatory site of GSK-3 inactivation, and indicate that glutamic acid cannot mimic the function of the phosphorylated residue. The GSK-3-expressing cell system enabled us to examine whether GSK-3 can induce changes in the endogenous glycogen synthase activity. A decrease in glycogen synthase activity (50%) was observed in cells expressing the S9A mutant. Similarly, glycogen synthase activity was suppressed in cells expressing WT and the S9E mutant (20-30%, respectively). These studies indicate that activation of GSK-3 is sufficient to inhibit glycogen synthase in intact cells, and provide evidence supporting a physiological role for GSK-3 in regulating glycogen synthase and glycogen metabolism.
Glycogen branching enzyme
GSK3B
Glycogen debranching enzyme
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GSK3B
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Glycogen synthase kinase-3β(GSK-3β) was initially identified as an enzyme involved in glycogen metabolism.GSK-3β phosphorylates a variety of substrates of different biological activities to regulate cellular functions,such as proliferation,differentiation and apoptosis.In the research model of the Parkinson's disease,the increase of GSK-3β activity was recently found to induce neuron apoptosis.On the other hand,when the GSK-3β activity was inhibited,both the tau protein phosphorylation and α-synuclein expression were reduced,then led to neural protection.Therefore,GSK-3β may become a new target for the treatment of Parkinson's disease.
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Abstract A series of 3‐aryl‐4‐pyrrolyl‐maleimides were designed, synthesized, and evaluated for their glycogen synthase kinase‐3β (GSK‐3β) inhibitory activity. Most compounds exhibited potent activity against GSK‐3β. Among them, compounds 11a , 11c , 11h , 11i , and 11j significantly reduced Aβ‐induced Tau hyperphosphorylation, showing the inhibition of GSK‐3β at the cellular level. Structure–activity relationships were discussed based on the experimental data obtained.
Hyperphosphorylation
GSK3B
Structure–activity relationship
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Glycogen synthase kinase-3 (GSK-3) is involved in signaling from the insulin receptor and inhibitors of it are expected to lower plasma glucose similar to insulin. It is under development for the treatment of type 2 diabetes. The target bisarylmaleimide was synthesized in seven steps in 33% overall yield from 5-fluoroindole (A).
GSK3B
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