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.
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