Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-α

Fabio Lo Monte, Thomas Kramer, Jiamin Gu, Upendra Rao Anumala, Luciana Marinelli, Valeria La Pietra, Ettore Novellino, Bénédicte Franco, David Demedts, Fred Van Leuven, Ana Fuertes, Juan Manuel Dominguez, Batya Plotkin, Hagit Eldar-Finkelman, Boris Schmidt

Research output: Contribution to journalArticlepeer-review


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-α and GSK-3β to AD pathology and AML is ongoing. Thus, the identification of potent GSK-α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-α 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-α 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.

Original languageEnglish
Pages (from-to)4407-4424
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - 10 May 2012


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