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Título

Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis

AutorSalado, Irene G. ; Redondo, Miriam ; Bello, Murilo L.; Pérez, Concepción; Liachko, Nicole F.; Kraemer, Brian C.; Miguel, Laetitia; Lecourtois, Magalie; Gil, Carmen ; Martínez, Ana ; Perez, Daniel I.
Fecha de publicación2014
CitaciónJournal of Medicinal Chemistry 57: 2755- 2772 (2014)
ResumenAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1δ inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood-brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved. © 2014 American Chemical Society.
URIhttp://hdl.handle.net/10261/96291
DOI10.1021/jm500065f
Identificadoresdoi: 10.1021/jm500065f
issn: 1520-4804
e-issn: 1520-4804
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