A Triazolotriazine-Based Dual GSK-3β/CK-1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition
| Autor: | Nicola Demitri, Giovanni Bottegoni, Rita De Zorzi, Stephanie Federico, Daniel I. Perez, Paola Storici, Concepción Pérez, Irene Marcovich, Andrea Cavalli, Ana Martínez, Giampiero Spalluto, Paola Bisignano, Maicol Bissaro, Sara Redenti, Teresa De Vita, Stefano Moro |
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| Přispěvatelé: | Redenti, Sara, Marcovich, Irene, De Vita, Teresa, Pérez, Concepción, De Zorzi, Rita, Demitri, Nicola, Perez, Daniel I., Bottegoni, Giovanni, Bisignano, Paola, Bissaro, Maicol, Moro, Stefano, Martinez, Ana, Storici, Paola, Spalluto, Giampiero, Cavalli, Andrea, Federico, Stephanie |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Cell Survival Parkinson's disease Toxicology and Pharmaceutics (all) Pharmacology Crystallography X-Ray Ligands PC12 Cells 01 natural sciences Neuroprotection Biochemistry casein kinase 1δ neuroinflammation Structure-Activity Relationship GSK-3 Drug Discovery Animals Humans General Pharmacology Toxicology and Pharmaceutics Protein Kinase Inhibitors IC50 chemistry.chemical_classification Glycogen Synthase Kinase 3 beta Dose-Response Relationship Drug Molecular Structure Triazines 010405 organic chemistry Kinase Drug Discovery3003 Pharmaceutical Science Organic Chemistry In vitro Rats 0104 chemical sciences thia-Michael reaction 010404 medicinal & biomolecular chemistry glycogen synthase kinase 3β Neuroprotective Agents Enzyme chemistry Docking (molecular) Casein Kinase Idelta Pharmacology Toxicology and Pharmaceutics (all) Molecular Medicine Casein kinase 1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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