Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease

Parkinson’s disease (PD), an age-related neurodegenerative disorder that results from a progressive loss of dopaminergic neurons has an enormous economical and human cost. Unfortunately, only symptomatic treatment such as dopamine replacement therapy is available. Therefore, drugs with new mechanism...

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Detalles Bibliográficos
Autores: Morales-García, José A., Salado, Irene G., Sanz-SanCristóbal, Marina, Gil, Carmen, Pérez Castillo, Ana, Martínez Gil, Ana, Pérez, Daniel I.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/154777
Acceso en línea:http://hdl.handle.net/10261/154777
Access Level:acceso abierto
Palabra clave:Drug discovery and Drug delivery systems
Heterocyclic compounds
Structure-activity relationship
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spelling Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s diseaseMorales-García, José A.Salado, Irene G.Sanz-SanCristóbal, MarinaGil, CarmenPérez Castillo, AnaMartínez Gil, AnaPérez, Daniel I.Drug discovery and Drug delivery systemsHeterocyclic compoundsStructure-activity relationshipParkinson’s disease (PD), an age-related neurodegenerative disorder that results from a progressive loss of dopaminergic neurons has an enormous economical and human cost. Unfortunately, only symptomatic treatment such as dopamine replacement therapy is available. Therefore, drugs with new mechanisms of action able to protect against neuronal cell death are an urgent need. We here report the in vivo efficacy on dopaminergic neuronal protection in a PD mouse model and the lack of toxicity in zebrafish and Ames test of benzothiazole-based casein kinase-1δ (CK-1δ) nanomolar inhibitors. On the basis of these results, we propose protein kinase CK-1δ inhibitors as the possible disease-modifying drugs for PD, benzothiazole 4 being a promising drug candidate for further development as a new therapy of this neurodegenerative disease.This work was supported by grants from MINECO (SAF2012-37979-C03-01 to A.M. and SAF2014-52940-R to A.P.-C.) and from MICINN (grant SAF2010-16365 to A.P.-C.). I.G.S. and D.I.P. acknowledge a pre- and postdoctoral fellowship from MICINN (FPI program) and CSIC (JAE program), respectively. CIBERNED is funded by the Instituto de Salud Carlos III. J.A.M.-G. is a fellow from CIBERNED.Peer reviewedAmerican Chemical SocietyMinisterio de Economía y Competitividad (España)Ministerio de Economía, Industria y Competitividad (España)Consejo Superior de Investigaciones Científicas (España)Instituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201720172017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/154777reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-52940-Rhttp://dx.doi.org/10.1021/acsomega.7b00869Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1547772026-05-22T06:33:51Z
dc.title.none.fl_str_mv Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
title Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
spellingShingle Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
Morales-García, José A.
Drug discovery and Drug delivery systems
Heterocyclic compounds
Structure-activity relationship
title_short Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
title_full Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
title_fullStr Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
title_full_unstemmed Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
title_sort Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease
dc.creator.none.fl_str_mv Morales-García, José A.
Salado, Irene G.
Sanz-SanCristóbal, Marina
Gil, Carmen
Pérez Castillo, Ana
Martínez Gil, Ana
Pérez, Daniel I.
author Morales-García, José A.
author_facet Morales-García, José A.
Salado, Irene G.
Sanz-SanCristóbal, Marina
Gil, Carmen
Pérez Castillo, Ana
Martínez Gil, Ana
Pérez, Daniel I.
author_role author
author2 Salado, Irene G.
Sanz-SanCristóbal, Marina
Gil, Carmen
Pérez Castillo, Ana
Martínez Gil, Ana
Pérez, Daniel I.
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Economía, Industria y Competitividad (España)
Consejo Superior de Investigaciones Científicas (España)
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Drug discovery and Drug delivery systems
Heterocyclic compounds
Structure-activity relationship
topic Drug discovery and Drug delivery systems
Heterocyclic compounds
Structure-activity relationship
description Parkinson’s disease (PD), an age-related neurodegenerative disorder that results from a progressive loss of dopaminergic neurons has an enormous economical and human cost. Unfortunately, only symptomatic treatment such as dopamine replacement therapy is available. Therefore, drugs with new mechanisms of action able to protect against neuronal cell death are an urgent need. We here report the in vivo efficacy on dopaminergic neuronal protection in a PD mouse model and the lack of toxicity in zebrafish and Ames test of benzothiazole-based casein kinase-1δ (CK-1δ) nanomolar inhibitors. On the basis of these results, we propose protein kinase CK-1δ inhibitors as the possible disease-modifying drugs for PD, benzothiazole 4 being a promising drug candidate for further development as a new therapy of this neurodegenerative disease.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/154777
url http://hdl.handle.net/10261/154777
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-52940-R
http://dx.doi.org/10.1021/acsomega.7b00869
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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