Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 6, Pages 2755-2772Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500065f
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Funding
- MINECO [SAF2012-37979-C03-01]
- Association Francaise contre les Myopathies [AFM-16169]
- Department of Veterans Affairs [1147891]
- CDA2 [I01BX007080]
- Ligue Europeenne Contre la Maladie d'Alzheimer (LECMA)
- National Institutes of Health [R01NS064131]
- MICINN (FPI program)
- CSIC (JAE program)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
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Amyotrophic 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-1 delta 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.
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