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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.

Author information

1
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgeri 1, 34127, Trieste, Italy.
2
Drug Discovery & Development (D3), Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.
3
Centro de Investigaciones Biologicas, CSIC, Avenida Ramiro de Maeztu 9, 28040, Madrid, Spain.
4
Elettra Sincrotrone Trieste S.C.p.A., SS 14, km 163.5, AREA Science Park, 34149, Trieste, Italy.
5
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.
6
Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA, 94158, USA.
7
Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.

Abstract

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.

KEYWORDS:

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

PMID:
30548443
DOI:
10.1002/cmdc.201800778

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