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

*Corresponding author for this work

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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