Identification of Glycogen Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase Kinase-3α
- 1 May 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 55 (9), 4407-4424
- https://doi.org/10.1021/jm300309a
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 14d and 15b showed the highest GSK-3α 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.Keywords
This publication has 49 references indexed in Scilit:
- Alzheimer's disease: strategies for disease modificationNature Reviews Drug Discovery, 2010
- 2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole Derivatives as Novel Inhibitors of Glycogen Synthase Kinase-3β with Good Brain PermeabilityJournal of Medicinal Chemistry, 2009
- Lithium, a Potential Protective Drug in Alzheimer’s DiseaseNeurodegenerative Diseases, 2008
- Preclinical efficacy on GSK‐3 inhibitors: Towards a future generation of powerful drugsMedicinal Research Reviews, 2008
- Untangling tau hyperphosphorylation in drug design for neurodegenerative diseasesNature Reviews Drug Discovery, 2007
- GSK3 inhibitors: development and therapeutic potentialNature Reviews Drug Discovery, 2004
- Glycogen synthase kinase 3: a drug target for CNS therapiesJournal of Neurochemistry, 2004
- Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammationMedicinal Research Reviews, 2002
- The renaissance of GSK3Nature Reviews Molecular Cell Biology, 2001
- GSK3 takes centre stage more than 20 years after its discoveryBiochemical Journal, 2001