Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma

This article belongs to the Section Drug Targeting and Design

Detalles Bibliográficos
Autores: Goñi, Irati de, Artetxe-Zurutuza, A., Elizazu, Joseba, García-García de Garayo, Raúl, Vergara-Arce, Jhonatan, Azkargorta, Mikel, Toledano-Pinedo, M., Porro-Pérez, Alicia, Elortza, Felix, Marco-Contelles, José, Sampron, N., Iturrioz-Rodríguez, Nerea, Matheu, Ander
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/412231
Acceso en línea:http://hdl.handle.net/10261/412231
Access Level:acceso abierto
Palabra clave:Glioblastoma
MSM
HDAC inhibition
Glioma stem cells
Proliferation
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spelling Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against GlioblastomaGoñi, Irati deArtetxe-Zurutuza, A.Elizazu, JosebaGarcía-García de Garayo, RaúlVergara-Arce, JhonatanAzkargorta, MikelToledano-Pinedo, M.Porro-Pérez, AliciaElortza, FelixMarco-Contelles, JoséSampron, N.Iturrioz-Rodríguez, NereaMatheu, AnderGlioblastomaMSMHDAC inhibitionGlioma stem cellsProliferationThis article belongs to the Section Drug Targeting and Design[Background/Objectives] Glioblastoma is the most common and aggressive primary brain tumor in adults, with patient prognosis remaining poor. Treatment resistance and tumor recurrence are frequent, primarily due to the high intra- and inter-tumoral heterogeneity and the existence of glioma stem cells. Thus, there is an urgent need for novel and more effective therapeutic strategies. Multitarget small molecules (MSMs) are emerging as a novel therapeutic strategy for the treatment of complex diseases such as cancer.[Methods] In the present work, we have generated a novel family of indole-based MSMs with pharmacophoric moieties combining the parent compounds Contilisant and the HDAC inhibitor Tubastatin A. Thus, the MSMs were designed to inhibit monoamine oxidases (MAOs), cholinesterases (ChEs) and histone deacetylases (HDACs), while acting as histamine H3 receptor (H3R) antagonists and sigma 1 receptor (S1R) agonists. We generated four different molecules and evaluated in detail the activity of the two most efficient MSM compounds in vitro and in vivo.[Results] These molecules induced potent cytotoxic effects in vitro in patient-derived glioma stem cells and glioblastoma cell lines and significantly impaired tumor growth in vivo. OMIC analyses further revealed that the compounds induce dysregulation of the cell cycle in glioma stem cells. Moreover, in silico analyses indicated that these compounds are theoretically capable of crossing the blood–brain barrier, while exhibiting low toxicity in healthy cells.[Conclusions] In conclusion, our findings demonstrate the potential antitumor activity of a novel family of MSMs in preclinical models of glioblastoma.A.A.-Z. received a predoctoral fellowship from the Education Department of the Basque Government (PRE_2020_1_0130). N.I.-R. is the recipient of a Sara Borrell postdoctoral contract (CD22/00076) from Carlos III Institute of Health. We thank the Histology Platform and Animal Facility of the Biogipuzkoa Health Research Institute for their support. This work was supported by the Instituto de Salud Carlos III (ISCIII) through the project PI19/01355, PI22/01905, FORT23-00026, DTS24/00153 and co-funded by the European Union and the Health Department of the Basque Country, with this funding awarded to AM.Peer reviewedMultidisciplinary Digital Publishing InstituteEusko JaurlaritzaInstituto de Salud Carlos IIIInstituto de Investigación Sanitaria BiogipuzkoaEuropean CommissionPorro-Pérez, Alicia [0000-0002-8310-1549]Marco-Contelles, José [0000-0003-0690-0328]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2026202620252026info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/412231reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/pharmaceutics17121594https://doi.org/10.3390/pharmaceutics17121594Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4122312026-05-22T06:33:51Z
dc.title.none.fl_str_mv Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
title Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
spellingShingle Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
Goñi, Irati de
Glioblastoma
MSM
HDAC inhibition
Glioma stem cells
Proliferation
title_short Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
title_full Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
title_fullStr Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
title_full_unstemmed Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
title_sort Generation and Characterization of Novel Contilisant+Tubastatin a Multitarget Small Molecules Against Glioblastoma
dc.creator.none.fl_str_mv Goñi, Irati de
Artetxe-Zurutuza, A.
Elizazu, Joseba
García-García de Garayo, Raúl
Vergara-Arce, Jhonatan
Azkargorta, Mikel
Toledano-Pinedo, M.
Porro-Pérez, Alicia
Elortza, Felix
Marco-Contelles, José
Sampron, N.
Iturrioz-Rodríguez, Nerea
Matheu, Ander
author Goñi, Irati de
author_facet Goñi, Irati de
Artetxe-Zurutuza, A.
Elizazu, Joseba
García-García de Garayo, Raúl
Vergara-Arce, Jhonatan
Azkargorta, Mikel
Toledano-Pinedo, M.
Porro-Pérez, Alicia
Elortza, Felix
Marco-Contelles, José
Sampron, N.
Iturrioz-Rodríguez, Nerea
Matheu, Ander
author_role author
author2 Artetxe-Zurutuza, A.
Elizazu, Joseba
García-García de Garayo, Raúl
Vergara-Arce, Jhonatan
Azkargorta, Mikel
Toledano-Pinedo, M.
Porro-Pérez, Alicia
Elortza, Felix
Marco-Contelles, José
Sampron, N.
Iturrioz-Rodríguez, Nerea
Matheu, Ander
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Eusko Jaurlaritza
Instituto de Salud Carlos III
Instituto de Investigación Sanitaria Biogipuzkoa
European Commission
Porro-Pérez, Alicia [0000-0002-8310-1549]
Marco-Contelles, José [0000-0003-0690-0328]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Glioblastoma
MSM
HDAC inhibition
Glioma stem cells
Proliferation
topic Glioblastoma
MSM
HDAC inhibition
Glioma stem cells
Proliferation
description This article belongs to the Section Drug Targeting and Design
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
2026
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/10261/412231
url http://hdl.handle.net/10261/412231
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/pharmaceutics17121594
https://doi.org/10.3390/pharmaceutics17121594
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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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score 15.811543

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