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

J Med Chem. 2014 Mar 27;57(6):2755-72. doi: 10.1021/jm500065f. Epub 2014 Mar 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Animals
  • Animals, Genetically Modified
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / pharmacology
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Casein Kinase I / antagonists & inhibitors*
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Drosophila
  • Drug Design
  • Drug Discovery
  • HEK293 Cells
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurotoxicity Syndromes / drug therapy
  • Phosphorylation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / therapeutic use*
  • Substrate Specificity


  • Benzothiazoles
  • DNA-Binding Proteins
  • Heterocyclic Compounds
  • Protein Kinase Inhibitors
  • Casein Kinase I