- SMALL MOLECULE INHIBITORS OF SUPEROXIDE DISMUTASE EXPRESSION
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Disclosed are new small molecules and the uses thereof for inhibiting superoxide dismutase (SOD) expression. Also disclosed are pharmaceutical compositions comprising the small molecule inhibitors which may be administered in methods of treating diseases or disorders associated with elevated SOD expression or activity, including neurological diseases and disorders such as amyotrophic lateral sclerosis (ALS).
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Paragraph 0076-0079
(2016/08/17)
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- SMALL MOLECULE INHIBITORS OF SUPEROXIDE DISMUTASE EXPRESSION
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Disclosed are new small molecules and the uses thereof for inhibiting superoxide dismutase (SOD) expression. Also disclosed are pharmaceutical compositions comprising the small molecule inhibitors which may be administered in methods of treating diseases or disorders associated with elevated SOD expression or activity, including neurological diseases and disorders such as amyotrophic lateral sclerosis (ALS).
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- Discovery of 1,3,4-oxidiazole scaffold compounds as inhibitors of superoxide dismutase expression
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The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide dismutase (SOD1) is responsible for about 10-15% of the genetically linked autosomal dominant disease. Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of 2-[3-iodophenyl) methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead compound with improved drug-like characteristics and activity. Development of small molecules that reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to familial ALS linked to gain of function mutations in other genes.
- Lukas, Thomas J.,Schiltz, Gary E.,Arrat, Hasan,Scheidt, Karl,Siddique, Teepu
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p. 1532 - 1537
(2014/03/21)
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- Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-α
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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.
- Lo Monte, Fabio,Kramer, Thomas,Gu, Jiamin,Anumala, Upendra Rao,Marinelli, Luciana,La Pietra, Valeria,Novellino, Ettore,Franco, Bénédicte,Demedts, David,Van Leuven, Fred,Fuertes, Ana,Dominguez, Juan Manuel,Plotkin, Batya,Eldar-Finkelman, Hagit,Schmidt, Boris
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experimental part
p. 4407 - 4424
(2012/08/13)
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- Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors
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Using a virtual screening strategy based on a methodology derived from the CATS molecular descriptor, a novel compound class with inhibitory activity against the GSK-3 enzyme was identified through scaffold hopping. These compounds were readily synthesize
- Narum, Lars,Norskov-Lauritsen, Leif,Olesen, Preben H.
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p. 1525 - 1528
(2007/10/03)
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