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ChemMedChem. 2018 Oct 25. doi: 10.1002/cmdc.201800632. [Epub ahead of print]

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?

Author information

1
ITALY.
2
University of Padova, Department of Pharmaceutical and Pharmacological Sciences, Molecular Modeling Section (MMS), Via Marzolo, 5, 35131, Padova, ITALY.

Abstract

Riluzole, approved by FDA in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, which mechanism of action is still obscure, mitigate ill progression with, unfortunately, a limited survival improvement. In the present work, for the first time, it has been demonstrated, using synergistically computational and in vitro studies, that riluzole is an ATP competitive inhibitor of the protein kinase CK1 isoform δ, with an IC50 value of 16.1 μM. This allows us to rewrite its possible molecular mechanism in the treatment of ALS. The inhibition of CK1δ catalytic activity indeed bridge together the two main pathological hallmarks of ALS: transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by glial excitatory amino acid transporter-2 (EAAT2) loss of expression.

KEYWORDS:

riluzole, ALS, protein kinase CK1δ, TDP-43, mechanism of action

PMID:
30359484
DOI:
10.1002/cmdc.201800632

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