A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition

Sara Redenti; Irene Marcovih; Teresa De Vita; Conception Perez; Rita De Zorzi; Nicola Demitri; Daniel I Perez; Giovanni Bottegoni; Paola Bisignano; Maicol Bissaro; Stefano Moro; Ana Martinez; Paola Storici; Giampiero Spalluto; Andrea Cavalli; Stephanie Federico

doi:10.1002/cmdc.201800778

A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition

Sara Redenti, Irene Marcovih, Teresa De Vita, Conception Perez, Rita De Zorzi, Nicola Demitri, Daniel I Perez, Giovanni Bottegoni, Paola Bisignano, Maicol Bissaro, Stefano Moro, Ana Martinez, Paola Storici, Giampiero Spalluto, Andrea Cavalli, Stephanie Federico

Pharmacy

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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 [IC ₅₀(GSK-3β)=0.17 μm; IC ₅₀(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.

Original language	English
Pages (from-to)	310-314
Number of pages	5
Journal	ChemMedChem
Volume	14
Issue number	3
Early online date	12 Dec 2018
DOIs	https://doi.org/10.1002/cmdc.201800778
Publication status	Published - 5 Feb 2019

Bibliographical note

S. Redenti, I. Marcovich, T. De Vita, C. Pérez, R. De Zorzi, N. Demitri, D. I. Perez, G. Bottegoni, P. Bisignano, M. Bissaro, S. Moro, A. Martinez, P. Storici, G. Spalluto, A. Cavalli, S. Federico, ChemMedChem 2019, 14, 310.

Keywords

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

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics(all)
Organic Chemistry

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Redenti, S., Marcovih, I., De Vita, T., Perez, C., De Zorzi, R., Demitri, N., Perez, D. I., Bottegoni, G., Bisignano, P., Bissaro, M., Moro, S., Martinez, A., Storici, P., Spalluto, G., Cavalli, A., & Federico, S. (2019). A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition. ChemMedChem, 14(3), 310-314. https://doi.org/10.1002/cmdc.201800778

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title = "A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition",

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 [IC 50(GSK-3β)=0.17 μm; IC 50(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 = "casein kinase 1δ, glycogen synthase kinase 3β, neuroinflammation, Parkinson's disease, thia-Michael reaction",

author = "Sara Redenti and Irene Marcovih and {De Vita}, Teresa and Conception Perez and {De Zorzi}, Rita and Nicola Demitri and Perez, {Daniel I} and Giovanni Bottegoni and Paola Bisignano and Maicol Bissaro and Stefano Moro and Ana Martinez and Paola Storici and Giampiero Spalluto and Andrea Cavalli and Stephanie Federico",

note = "S. Redenti, I. Marcovich, T. De Vita, C. P{\'e}rez, R. De Zorzi, N. Demitri, D. I. Perez, G. Bottegoni, P. Bisignano, M. Bissaro, S. Moro, A. Martinez, P. Storici, G. Spalluto, A. Cavalli, S. Federico, ChemMedChem 2019, 14, 310.",

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Redenti, S, Marcovih, I, De Vita, T, Perez, C, De Zorzi, R, Demitri, N, Perez, DI, Bottegoni, G, Bisignano, P, Bissaro, M, Moro, S, Martinez, A, Storici, P, Spalluto, G, Cavalli, A & Federico, S 2019, 'A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition', ChemMedChem, vol. 14, no. 3, pp. 310-314. https://doi.org/10.1002/cmdc.201800778

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T1 - A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition

AU - Redenti, Sara

AU - Marcovih, Irene

AU - De Vita, Teresa

AU - Perez, Conception

AU - De Zorzi, Rita

AU - Demitri, Nicola

AU - Perez, Daniel I

AU - Bottegoni, Giovanni

AU - Bisignano, Paola

AU - Bissaro, Maicol

AU - Moro, Stefano

AU - Martinez, Ana

AU - Storici, Paola

AU - Spalluto, Giampiero

AU - Cavalli, Andrea

AU - Federico, Stephanie

N1 - S. Redenti, I. Marcovich, T. De Vita, C. Pérez, R. De Zorzi, N. Demitri, D. I. Perez, G. Bottegoni, P. Bisignano, M. Bissaro, S. Moro, A. Martinez, P. Storici, G. Spalluto, A. Cavalli, S. Federico, ChemMedChem 2019, 14, 310.

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N2 - 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 [IC 50(GSK-3β)=0.17 μm; IC 50(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.

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KW - casein kinase 1δ

KW - glycogen synthase kinase 3β

KW - neuroinflammation

KW - Parkinson's disease

KW - thia-Michael reaction

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ER -

A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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