Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity

Alamón, Catalina - Dávila Saralegui, Belén - García Melián, María Fernanda - Sánchez, Carina - Kovacs, Mariángeles - Trias, Emiliano - Barbeito, Luis - Gabay, Martín - Zeineh, Nidal - Gavish, Moshe - Teixidor, Francesc - Viñas, Clara - Couto, Marcos - Cerecetto, Hugo

Resumen:

Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.


Detalles Bibliográficos
2020
Carborane
FLT3
Sub-G1 arrest
Anti-tumor activity
Inglés
Universidad de la República
COLIBRI
https://hdl.handle.net/20.500.12008/31990
Acceso abierto
Licencia Creative Commons Atribución (CC - By 4.0)
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author Alamón, Catalina
author2 Dávila Saralegui, Belén
García Melián, María Fernanda
Sánchez, Carina
Kovacs, Mariángeles
Trias, Emiliano
Barbeito, Luis
Gabay, Martín
Zeineh, Nidal
Gavish, Moshe
Teixidor, Francesc
Viñas, Clara
Couto, Marcos
Cerecetto, Hugo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author_facet Alamón, Catalina
Dávila Saralegui, Belén
García Melián, María Fernanda
Sánchez, Carina
Kovacs, Mariángeles
Trias, Emiliano
Barbeito, Luis
Gabay, Martín
Zeineh, Nidal
Gavish, Moshe
Teixidor, Francesc
Viñas, Clara
Couto, Marcos
Cerecetto, Hugo
author_role author
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http://localhost:8080/xmlui/bitstream/20.500.12008/31990/1/10.3390cancers12113423.pdf
collection COLIBRI
dc.contributor.filiacion.none.fl_str_mv Alamón Catalina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.
Dávila Saralegui Belén, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.
García Melián María Fernanda, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.
Sánchez Carina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.
Kovacs Mariángeles, Institut Pasteur (Montevideo)
Trias Emiliano, Institut Pasteur (Montevideo)
Barbeito Luis, Institut Pasteur (Montevideo)
Gabay Martín
Zeineh Nidal
Gavish Moshe
Teixidor Francesc
Viñas Clara
Couto Marcos, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.
Cerecetto Hugo, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.
dc.creator.none.fl_str_mv Alamón, Catalina
Dávila Saralegui, Belén
García Melián, María Fernanda
Sánchez, Carina
Kovacs, Mariángeles
Trias, Emiliano
Barbeito, Luis
Gabay, Martín
Zeineh, Nidal
Gavish, Moshe
Teixidor, Francesc
Viñas, Clara
Couto, Marcos
Cerecetto, Hugo
dc.date.accessioned.none.fl_str_mv 2022-06-14T13:03:56Z
dc.date.available.none.fl_str_mv 2022-06-14T13:03:56Z
dc.date.issued.none.fl_str_mv 2020
dc.description.abstract.none.fl_txt_mv Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.
dc.format.extent.es.fl_str_mv 21 h.
dc.format.mimetype.es.fl_str_mv application/pdf
dc.identifier.citation.es.fl_str_mv Alamón, C, Dávila Saralegui, B, García Melián, M, [y otros] "Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity". Cancers. [en línea] 2020, 12(11): 3423. 21 h. DOI: 10.3390/cancers12113423
dc.identifier.doi.none.fl_str_mv 10.3390/cancers12113423
dc.identifier.issn.none.fl_str_mv 2072-6694
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/20.500.12008/31990
dc.language.iso.none.fl_str_mv en
eng
dc.publisher.es.fl_str_mv MDPI
dc.relation.ispartof.es.fl_str_mv Cancers, 2020, 12(11): 3423
dc.rights.license.none.fl_str_mv Licencia Creative Commons Atribución (CC - By 4.0)
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
dc.source.none.fl_str_mv reponame:COLIBRI
instname:Universidad de la República
instacron:Universidad de la República
dc.subject.en.fl_str_mv Sub-G1 arrest
Anti-tumor activity
dc.subject.es.fl_str_mv Carborane
FLT3
dc.title.none.fl_str_mv Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
dc.type.es.fl_str_mv Artículo
dc.type.none.fl_str_mv info:eu-repo/semantics/article
dc.type.version.none.fl_str_mv info:eu-repo/semantics/publishedVersion
description Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.
eu_rights_str_mv openAccess
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id COLIBRI_bbc0d4e8895cbcfd6d3492bebf32a37b
identifier_str_mv Alamón, C, Dávila Saralegui, B, García Melián, M, [y otros] "Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity". Cancers. [en línea] 2020, 12(11): 3423. 21 h. DOI: 10.3390/cancers12113423
2072-6694
10.3390/cancers12113423
instacron_str Universidad de la República
institution Universidad de la República
instname_str Universidad de la República
language eng
language_invalid_str_mv en
network_acronym_str COLIBRI
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publishDate 2020
reponame_str COLIBRI
repository.mail.fl_str_mv mabel.seroubian@seciu.edu.uy
repository.name.fl_str_mv COLIBRI - Universidad de la República
repository_id_str 4771
rights_invalid_str_mv Licencia Creative Commons Atribución (CC - By 4.0)
spelling Alamón Catalina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Dávila Saralegui Belén, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.García Melián María Fernanda, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.Sánchez Carina, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Kovacs Mariángeles, Institut Pasteur (Montevideo)Trias Emiliano, Institut Pasteur (Montevideo)Barbeito Luis, Institut Pasteur (Montevideo)Gabay MartínZeineh NidalGavish MosheTeixidor FrancescViñas ClaraCouto Marcos, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Cerecetto Hugo, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.2022-06-14T13:03:56Z2022-06-14T13:03:56Z2020Alamón, C, Dávila Saralegui, B, García Melián, M, [y otros] "Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity". Cancers. [en línea] 2020, 12(11): 3423. 21 h. DOI: 10.3390/cancers121134232072-6694https://hdl.handle.net/20.500.12008/3199010.3390/cancers12113423Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being—especially for glioblastomas—extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood–brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.Submitted by Verdun Juan Pablo (jverdun@fcien.edu.uy) on 2022-06-13T16:49:59Z No. of bitstreams: 2 license_rdf: 19875 bytes, checksum: 9fdbed07f52437945402c4e70fa4773e (MD5) 10.3390cancers12113423.pdf: 5603806 bytes, checksum: 105210021842c68e20b999fd047d41d5 (MD5)Approved for entry into archive by Faget Cecilia (lfaget@fcien.edu.uy) on 2022-06-14T12:53:18Z (GMT) No. of bitstreams: 2 license_rdf: 19875 bytes, checksum: 9fdbed07f52437945402c4e70fa4773e (MD5) 10.3390cancers12113423.pdf: 5603806 bytes, checksum: 105210021842c68e20b999fd047d41d5 (MD5)Made available in DSpace by Luna Fabiana (fabiana.luna@seciu.edu.uy) on 2022-06-14T13:03:56Z (GMT). No. of bitstreams: 2 license_rdf: 19875 bytes, checksum: 9fdbed07f52437945402c4e70fa4773e (MD5) 10.3390cancers12113423.pdf: 5603806 bytes, checksum: 105210021842c68e20b999fd047d41d5 (MD5) Previous issue date: 202021 h.application/pdfenengMDPICancers, 2020, 12(11): 3423Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución (CC - By 4.0)CarboraneFLT3Sub-G1 arrestAnti-tumor activitySunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activityArtículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionreponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaAlamón, CatalinaDávila Saralegui, BelénGarcía Melián, María FernandaSánchez, CarinaKovacs, MariángelesTrias, EmilianoBarbeito, LuisGabay, MartínZeineh, NidalGavish, MosheTeixidor, FrancescViñas, ClaraCouto, MarcosCerecetto, HugoLICENSElicense.txtlicense.txttext/plain; charset=utf-84267http://localhost:8080/xmlui/bitstream/20.500.12008/31990/5/license.txt6429389a7df7277b72b7924fdc7d47a9MD55CC-LICENSElicense_urllicense_urltext/plain; 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- Universidad de la Repúblicafalse
spellingShingle Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
Alamón, Catalina
Carborane
FLT3
Sub-G1 arrest
Anti-tumor activity
status_str publishedVersion
title Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
title_full Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
title_fullStr Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
title_full_unstemmed Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
title_short Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
title_sort Sunitinib-containing carborane pharmacophore with the ability to inhibit tyrosine kinases receptors FLT3, KIT and PDGFR-β, exhibits powerful in vivo anti-glioblastoma activity
topic Carborane
FLT3
Sub-G1 arrest
Anti-tumor activity
url https://hdl.handle.net/20.500.12008/31990