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ChemMedChem. 2018 Dec 12. doi: 10.1002/cmdc.201800778. [Epub ahead of print]

A Triazolotriazine-Based Dual GSK-3β/CK-1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition.

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Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgeri 1, 34127, Trieste, Italy.
Drug Discovery & Development (D3), Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.
Centro de Investigaciones Biologicas, CSIC, Avenida Ramiro de Maeztu 9, 28040, Madrid, Spain.
Elettra Sincrotrone Trieste S.C.p.A., SS 14, km 163.5, AREA Science Park, 34149, Trieste, Italy.
School of Pharmacy-Institute of Clinical Sciences, College of Medical and Dental Sciences, Sir Robert Aitken Institute for Medical Research, University of Birmingham, Edgbaston, B15 2TT, UK.
Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA, 94158, USA.
Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.


Glycogen synthase kinase 3β (GSK-3β) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC50 (GSK-3β)=0.17 μm; IC50 (CK-1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.


Parkinson's disease; casein kinase 1δ; glycogen synthase kinase 3β; neuroinflammation; thia-Michael reaction


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