A unique type of GSK-3 inhibitor brings new opportunities to the clinic

@article{LichtMurava2016AUT,
  title={A unique type of GSK-3 inhibitor brings new opportunities to the clinic},
  author={Avital Licht-Murava and Rom Paz and Lilach Vaks and Limor Avrahami and Batya Plotkin and Miriam Eisenstein and Hagit Eldar-Finkelman},
  journal={Science Signaling},
  year={2016},
  volume={9},
  pages={ra110 - ra110}
}
A substrate peptide that the kinase GSK-3 converts into its own inhibitor improves symptoms and cognitive function in an Alzheimer’s disease model. GSK-3 makes its own inhibitor One of the main challenges in developing kinase inhibitors has been achieving specificity. Licht-Murava et al. discovered a substrate peptide derivative, L807, that the kinase GSK-3 converted into an inhibitor within the catalytic site of the enzyme. This peptide was highly selective for GSK-3 when tested against a… 
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References

SHOWING 1-10 OF 99 REFERENCES
GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS
TLDR
The variety of GSK-3 inhibitors are described with a specific emphasis on their biological activities in neurons and neurological disorders and the available data raise the hope that one or more of these drug design approaches will prove successful at stabilizing or reversing the aberrant neuropathology and cognitive deficits of certain central nervous system disorders.
Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.
TLDR
Highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders, open the way for exclusive analyses of the function of GSK2 kinases in multiple signaling pathways involved in many prevalent disorders.
Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3
TLDR
It is shown that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of G SKS-3 inhibitors for AD therapeutics.
Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis and glycogen synthase kinase-3 inhibitors
TLDR
The present review discusses the potential of GSK-3 inhibitors for Alzheimer’s disease therapy, as well as some of their potential problems.
Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer's Disease
TLDR
The data from both approaches suggest that GSK-3α contributes to both SP and NFT pathogenesis while G SK-3β only modulates NFT formation, suggesting common but also different targets for both isoforms.
Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.
TLDR
Preliminary PET imaging studies in non-human primates confirmed that the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding, are overcome.
The selectivity of protein kinase inhibitors: a further update.
TLDR
Harmine has been identified as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro and the results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes.
Insulin Mimetic Action of Synthetic Phosphorylated Peptide Inhibitors of Glycogen Synthase Kinase-3
TLDR
A novel class of specific phosphorylated peptides inhibitors of GSK-3, which in sharp contrast to other protein kinase inhibitors that are ATP analogs, are substrate-competitive, are presented.
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