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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A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition. / Redenti, Sara; Marcovih, Irene; De Vita, Teresa; Perez, Conception; 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.

In: ChemMedChem, Vol. 14, No. 3, 05.02.2019, p. 310-314.

Research output: Contribution to journalArticle

Harvard

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

APA

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

Vancouver

Author

Redenti, Sara ; Marcovih, Irene ; De Vita, Teresa ; Perez, Conception ; 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. / A triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential neuroprotective agent presenting two different mechanisms of enzymatic inhibition. In: ChemMedChem. 2019 ; Vol. 14, No. 3. pp. 310-314.

Bibtex

@article{8f88bc943adf4d218a14752b8499c5aa,
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.",
year = "2019",
month = feb
day = "5",
doi = "10.1002/cmdc.201800778",
language = "English",
volume = "14",
pages = "310--314",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "Wiley-VCH Verlag",
number = "3",

}

RIS

TY - JOUR

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.

PY - 2019/2/5

Y1 - 2019/2/5

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.

AB - 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.

KW - casein kinase 1δ

KW - glycogen synthase kinase 3β

KW - neuroinflammation

KW - Parkinson's disease

KW - thia-Michael reaction

UR - http://www.scopus.com/inward/record.url?scp=85060180817&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201800778

DO - 10.1002/cmdc.201800778

M3 - Article

C2 - 30548443

VL - 14

SP - 310

EP - 314

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 3

ER -