Generation and validation of a novel multitarget small molecule in glioblastoma
Abstract 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 heterogen...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07569-1 |
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| author | Aizpea Artetxe-Zurutuza Nerea Iturrioz-Rodriguez Joseba Elizazu Mireia Toledano-Pinedo Alicia Porro-Pérez Irati De Goñi Alejandro Elua-Pinin Linda Schäker-Hübner Mikel Azkargorta Felix Elortza Isabel Iriepa Francisco Lòpez-Muñoz Veronica Moncho-Amor Finn K. Hansen Nicolás Sampron Jose Luis Marco-Contelles Ander Matheu |
| author_facet | Aizpea Artetxe-Zurutuza Nerea Iturrioz-Rodriguez Joseba Elizazu Mireia Toledano-Pinedo Alicia Porro-Pérez Irati De Goñi Alejandro Elua-Pinin Linda Schäker-Hübner Mikel Azkargorta Felix Elortza Isabel Iriepa Francisco Lòpez-Muñoz Veronica Moncho-Amor Finn K. Hansen Nicolás Sampron Jose Luis Marco-Contelles Ander Matheu |
| author_sort | Aizpea Artetxe-Zurutuza |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-5bef5594cdc14d1587cf3918eaef5494 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-5bef5594cdc14d1587cf3918eaef54942025-08-20T03:08:12ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111410.1038/s41419-025-07569-1Generation and validation of a novel multitarget small molecule in glioblastomaAizpea Artetxe-Zurutuza0Nerea Iturrioz-Rodriguez1Joseba Elizazu2Mireia Toledano-Pinedo3Alicia Porro-Pérez4Irati De Goñi5Alejandro Elua-Pinin6Linda Schäker-Hübner7Mikel Azkargorta8Felix Elortza9Isabel Iriepa10Francisco Lòpez-Muñoz11Veronica Moncho-Amor12Finn K. Hansen13Nicolás Sampron14Jose Luis Marco-Contelles15Ander Matheu16Cellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteCellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteCellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteLaboratory of Medicinal Chemistry (Institute of General Organic Chemistry, CSIC)Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry, CSIC)Cellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteCellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteDepartment of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of BonnProteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehdProteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehdAlcala University, Department of Organic and Inorganic Chemistry, Andrés M. del Río Chemistry Research Institute (IQAR); and DISCOBAC group, Castilla-La Mancha Health Research Institute (IDISCAM)Faculty of Health Sciences–HM Hospitals, Camilo José Cela University; HM Hospitals Health Research Institute; Neuropsychopharmacology Unit, “Hospital 12 de Octubre” Research InstituteCellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteDepartment of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of BonnCellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteLaboratory of Medicinal Chemistry (Institute of General Organic Chemistry, CSIC)Cellular Oncology group, Biogipuzkoa (Biodonostia) Health Research InstituteAbstract 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.https://doi.org/10.1038/s41419-025-07569-1 |
| spellingShingle | Aizpea Artetxe-Zurutuza Nerea Iturrioz-Rodriguez Joseba Elizazu Mireia Toledano-Pinedo Alicia Porro-Pérez Irati De Goñi Alejandro Elua-Pinin Linda Schäker-Hübner Mikel Azkargorta Felix Elortza Isabel Iriepa Francisco Lòpez-Muñoz Veronica Moncho-Amor Finn K. Hansen Nicolás Sampron Jose Luis Marco-Contelles Ander Matheu Generation and validation of a novel multitarget small molecule in glioblastoma Cell Death and Disease |
| title | 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_short | Generation and validation of a novel multitarget small molecule in glioblastoma |
| title_sort | generation and validation of a novel multitarget small molecule in glioblastoma |
| url | https://doi.org/10.1038/s41419-025-07569-1 |
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