Generation and validation of a novel multitarget small molecule in glioblastoma
The development of multitarget small molecules (MSMs) has emerged as a powerful strategy for the treatment of multifactorial diseases such as cancer. Glioblastoma is the most prevalent and malignant primary brain tumor in adults, which is characterized by poor prognosis and a high heterogeneity. Cur...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| 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:10261/387951 |
| Acceso en línea: | http://hdl.handle.net/10261/387951 |
| Access Level: | acceso abierto |
| id |
ES_42b0fa3cfe165dddd0dc81df7c2c0ce8 |
|---|---|
| oai_identifier_str |
oai:digital.csic.es:10261/387951 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
Generation and validation of a novel multitarget small molecule in glioblastomaArtetxe-Zurutuza, A.Iturrioz-Rodriguez, N.Elizazu, J.Toledano-Pinedo, MireiaPorro-Pérez, A.De Goñi, I.Elua-Pinin, A.Schäker-Hübner, L.Azkargorta, M.Elortza, F.Lòpez-Muñoz, F.Moncho-Amor, VerónicaHansen, F. K.Sampron, N.Marco-Contelles, JoséMatheu, A.The development of multitarget small molecules (MSMs) has emerged as a powerful strategy for the treatment of multifactorial diseases such as cancer. Glioblastoma is the most prevalent and malignant primary brain tumor in adults, which is characterized by poor prognosis and a high heterogeneity. Current standards of treatment present limited effectiveness, as patients develop therapy resistance and recur. In this work, we synthesized and characterized a novel multi-target molecule (named DDI199 or contilistat), which is a polyfunctionalized indole derivative developed by juxtaposing selected pharmacophoric moieties of the parent compounds Contilisant and Vorinostat (SAHA) to act as multifunctional ligands that inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs), and modulate histamine H3 (H3R) and Sigma 1 Receptor (S1R) receptors. DDI199 exerts high cytotoxic activity in conventional glioblastoma cell lines and patient-derived glioma stem cells in vitro. Importantly, it significantly reduces tumor growth in vivo, both alone and in combination with temozolomide (TMZ). The comparison with SAHA showed higher target specificity and antitumor activity of the new molecule. Transcriptomic and proteomic analyses of patient-derived glioma stem cells revealed a deregulation in cell cycle, DNA remodeling and neurotransmission activity by the treatment with DDI199. In conclusion, our data reveal the efficacy of a novel MSM in glioblastoma pre-clinical setting.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) and V. M-A by Miguel Servet contract (CP23/ 00111) from Carlos III Institute of Health. LSH wants to gratefully acknowledge experimental support by Philipp Stegen. The authors thank the Neurooncology Committee of the Donostia Hospital and the Animal facility and Pathology Service of Biogipuzkoa Institute for their help. This work was supported by grants from Carlos III Institute of Health and the European Regional Development Fund (PI19/01355, PI22/ 01905, DTS24/00153) and Health Department of the Basque Country (2022333034, 2023333012) to AM, AEI (PID2019-105813RB-C21) and UCJC (MITOPI) (2022) to JMC, and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) −GRK2873 (494832089) to L.S-H and FK.H.Nature Publishing GroupEusko JaurlaritzaInstituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (España)German Research FoundationConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2025202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/387951reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105813RB-C21http://dx.doi.org/10.1038/s41419-025-07569-1Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3879512026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| title |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| spellingShingle |
Generation and validation of a novel multitarget small molecule in glioblastoma Artetxe-Zurutuza, A. |
| title_short |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| title_full |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| title_fullStr |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| title_full_unstemmed |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| title_sort |
Generation and validation of a novel multitarget small molecule in glioblastoma |
| dc.creator.none.fl_str_mv |
Artetxe-Zurutuza, A. Iturrioz-Rodriguez, N. Elizazu, J. Toledano-Pinedo, Mireia Porro-Pérez, A. De Goñi, I. Elua-Pinin, A. Schäker-Hübner, L. Azkargorta, M. Elortza, F. Lòpez-Muñoz, F. Moncho-Amor, Verónica Hansen, F. K. Sampron, N. Marco-Contelles, José Matheu, A. |
| author |
Artetxe-Zurutuza, A. |
| author_facet |
Artetxe-Zurutuza, A. Iturrioz-Rodriguez, N. Elizazu, J. Toledano-Pinedo, Mireia Porro-Pérez, A. De Goñi, I. Elua-Pinin, A. Schäker-Hübner, L. Azkargorta, M. Elortza, F. Lòpez-Muñoz, F. Moncho-Amor, Verónica Hansen, F. K. Sampron, N. Marco-Contelles, José Matheu, A. |
| author_role |
author |
| author2 |
Iturrioz-Rodriguez, N. Elizazu, J. Toledano-Pinedo, Mireia Porro-Pérez, A. De Goñi, I. Elua-Pinin, A. Schäker-Hübner, L. Azkargorta, M. Elortza, F. Lòpez-Muñoz, F. Moncho-Amor, Verónica Hansen, F. K. Sampron, N. Marco-Contelles, José Matheu, A. |
| author2_role |
author author author 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 Ministerio de Ciencia e Innovación (España) German Research Foundation Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| description |
The development of multitarget small molecules (MSMs) has emerged as a powerful strategy for the treatment of multifactorial diseases such as cancer. Glioblastoma is the most prevalent and malignant primary brain tumor in adults, which is characterized by poor prognosis and a high heterogeneity. Current standards of treatment present limited effectiveness, as patients develop therapy resistance and recur. In this work, we synthesized and characterized a novel multi-target molecule (named DDI199 or contilistat), which is a polyfunctionalized indole derivative developed by juxtaposing selected pharmacophoric moieties of the parent compounds Contilisant and Vorinostat (SAHA) to act as multifunctional ligands that inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs), and modulate histamine H3 (H3R) and Sigma 1 Receptor (S1R) receptors. DDI199 exerts high cytotoxic activity in conventional glioblastoma cell lines and patient-derived glioma stem cells in vitro. Importantly, it significantly reduces tumor growth in vivo, both alone and in combination with temozolomide (TMZ). The comparison with SAHA showed higher target specificity and antitumor activity of the new molecule. Transcriptomic and proteomic analyses of patient-derived glioma stem cells revealed a deregulation in cell cycle, DNA remodeling and neurotransmission activity by the treatment with DDI199. In conclusion, our data reveal the efficacy of a novel MSM in glioblastoma pre-clinical setting. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025 2025 2025 |
| 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/10261/387951 |
| url |
http://hdl.handle.net/10261/387951 |
| 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/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105813RB-C21 http://dx.doi.org/10.1038/s41419-025-07569-1 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Nature Publishing Group |
| publisher.none.fl_str_mv |
Nature Publishing Group |
| 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 |
|
| _version_ |
1869406957329186816 |
| score |
15,811543 |