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Title: Identification of Glycogen Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase Kinase-3 alpha
Authors: Lo Monte, Fabio ×
Kramer, Thomas
Anumala, Upendra Rao
Marinelli, Luciana
La Pietra, Valeria
Novellino, Ettore
Franco, Benedicte
Demedts, David
Van Leuven, Fred
Fuertes, Ana
Manuel Dominguez, Juan
Plotkin, Batya
Eldar-Finkelman, Hagit
Schmidt, Boris #
Issue Date: May-2012
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:55 issue:9 pages:4407-4424
Abstract: The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-3 alpha and GSK-3 beta to AD pathology and AML is ongoing. Thus, the identification of potent GSK-3 alpha-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-3 alpha inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK-3 alpha selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Experimental Genetics and Transgenesis (-)
× corresponding author
# (joint) last author

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