Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?
ChemMedChem
; 13(24): 2601-2605, 2018 12 20.
Article
em En
| MEDLINE
| ID: mdl-30359484
ABSTRACT
Riluzole, approved by the US Food and Drug Administration (FDA) in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, whose mechanism of action is still obscure, mitigates progression of the illness, but unfortunately with only limited improvements. Herein we report the first demonstration, using a combination of computational and in vitro studies, that riluzole is an ATP-competitive inhibitor of the protein kinase CK1 isoformâ
δ, with an IC50 value of 16.1â
µm. This allows us to rewrite its possible molecular mechanism of action in the treatment of ALS. The inhibition of CK1δ catalytic activity indeed links the two main pathological hallmarks of ALS transactive response DNA-binding protein of 43â
kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by the loss of expression of glial excitatory amino acid transporter-2 (EAAT2).
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Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
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Riluzol
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Caseína Quinase Idelta
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Esclerose Lateral Amiotrófica
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article