title: Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-3α.
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-3α and GSK-3β to AD pathology and AML is ongoing. Thus, the identification of potent GSK-3α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-3α 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-3α 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.
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Germany. Fabio.Lo-Monte@gmx.de
authors.forename: Fabio
authors.initials: F
authors.lastname: Lo Monte
authors.forename: Thomas
authors.initials: T
authors.lastname: Kramer
authors.forename: Jiamin
authors.initials: J
authors.lastname: Gu
authors.forename: Upendra Rao
authors.initials: UR
authors.lastname: Anumala
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Franco
authors.forename: David
authors.initials: D
authors.lastname: Demedts
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Ana
authors.initials: A
authors.lastname: Fuertes
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Dominguez
authors.forename: Batya
authors.initials: B
authors.lastname: Plotkin
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha