Mixed-reversible and covalent kinase inhibition as a possible new strategy to treat neuro-inflammatory/degenerative diseases

Dual GSK-3β/CK-1δ inhibition could be a potential strategy to treat neurodegenerative diseases like Parkinson’s disease (PD). In order to validate this hypothesis, an inhibitor able to target both kinases in the submicromolar range was developed by docking-based design. In particular, thanks to x-ray crystallography, it was possible to observe for the first time a covalent interaction with Cys199 residue, identifying compound as a covalent GSK-3β inhibitor. Neuroprotection observed in preliminary studies on a PD model encourages further investigations on this dual target inhibition.