title: Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis.
abstract: 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-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.
authors.affiliation: Instituto de Química Médica, CSIC , Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Irene G
authors.initials: IG
authors.lastname: Salado
authors.forename: Miriam
authors.initials: M
authors.lastname: Redondo
authors.forename: Murilo L
authors.initials: ML
authors.lastname: Bello
authors.forename: Concepción
authors.initials: C
authors.lastname: Perez
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Liachko
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
authors.forename: Laetitia
authors.initials: L
authors.lastname: Miguel
authors.forename: Magalie
authors.initials: M
authors.lastname: Lecourtois
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D030801:Animals, Genetically Modified; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D047389:Casein Kinase I / Q000037:antagonists & inhibitors*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila; D015195:Drug Design; D055808:Drug Discovery; D057809:HEK293 Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use*; D013379:Substrate Specificity
chemical_list: D052160:Benzothiazoles; D004268:DNA-Binding Proteins; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D047389:Casein Kinase I