Identification of Glycogen
Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase
Kinase-3α
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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 <b>14d</b> and <b>15b</b> showed
the highest GSK-3α selectivity reported so far. In addition,
compound <b>14d</b> 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