Identification of Glycogen Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase Kinase-3 alpha
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 #
Journal of Medicinal Chemistry vol:55 issue:9 pages:4407-4424
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.