Identification of Glycogen Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase Kinase-3伪

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• 作者：Fabio Lo Monte ; Thomas Kramer ; Jiamin Gu ; Upendra Rao Anumala ; Luciana Marinelli ; Valeria La Pietra ; Ettore Novellino ; B茅n茅dicte Franco ; David Demedts ; Fred Van Leuven ; Ana Fuertes ; Juan Manuel Dominguez ; Batya Plotkin ; Hagit Eldar-Finkelman ; Boris Schmidt
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4407-4424
• 全文大小：754K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

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鈥檚 disease (AD). The debate on the respective contributions of GSK-3伪 and GSK-3尾 to AD pathology and AML is ongoing. Thus, the identification of potent GSK-3伪-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-3伪 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伪 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.