Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polyp...

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Detalles Bibliográficos
Autores: Hu, Huabin, Serra, Carme, Zhang, Wenjie, Scrivo, Aurora, Fernández Carasa, Irene, Consiglio, Antonella, Aytés Meneses, Álvaro, Pujana Genestar, M. Ángel, Llebaria Soldevila, Amadeu, Antolin, Albert A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/215772
Acceso en línea:https://hdl.handle.net/2445/215772
Access Level:acceso abierto
Palabra clave:Medicaments antineoplàstics
Càncer de pròstata
Farmacologia
Metabòlits
Antineoplastic agents
Prostate cancer
Pharmacology
Metabolites
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oai_identifier_str oai:recercat.cat:2445/215772
network_acronym_str ES
network_name_str España
repository_id_str
spelling Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metaboliteHu, HuabinSerra, CarmeZhang, WenjieScrivo, AuroraFernández Carasa, IreneConsiglio, AntonellaAytés Meneses, ÁlvaroPujana Genestar, M. ÁngelLlebaria Soldevila, AmadeuAntolin, Albert A.Medicaments antineoplàsticsCàncer de pròstataFarmacologiaMetabòlitsAntineoplastic agentsProstate cancerPharmacologyMetabolitesThe (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polypharmacology of M324, the major metabolite of the PARP1 inhibitor rucaparib. We demonstrate that M324 displays unique PLK2 inhibition at clinical concentrations. This kinase activity could have implications for the efficacy and safety of rucaparib and therefore warrants further clinical investigation. Importantly, we identify synergy between the drug and the metabolite in prostate cancer models and a complete reduction of α-synuclein accumulation in Parkinson's disease models. These activities could be harnessed in the clinic or open new drug discovery opportunities. The study reported here highlights the importance of characterizing the activity of drug metabolites to comprehensively understand drug response in the clinic and exploit our current drug arsenal in precision medicine.Cell Press2024202420242024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion21 p.application/pdfhttps://hdl.handle.net/2445/215772Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.chembiol.2024.01.007Cell Chemical Biology, 2024, vol. 31, num.5, p. 973-988https://doi.org/10.1016/j.chembiol.2024.01.007cc-by (c) Hu, Huabin et al., 2024https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2157722026-05-29T05:05:01Z
dc.title.none.fl_str_mv Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
title Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
spellingShingle Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
Hu, Huabin
Medicaments antineoplàstics
Càncer de pròstata
Farmacologia
Metabòlits
Antineoplastic agents
Prostate cancer
Pharmacology
Metabolites
title_short Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
title_full Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
title_fullStr Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
title_full_unstemmed Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
title_sort Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite
dc.creator.none.fl_str_mv Hu, Huabin
Serra, Carme
Zhang, Wenjie
Scrivo, Aurora
Fernández Carasa, Irene
Consiglio, Antonella
Aytés Meneses, Álvaro
Pujana Genestar, M. Ángel
Llebaria Soldevila, Amadeu
Antolin, Albert A.
author Hu, Huabin
author_facet Hu, Huabin
Serra, Carme
Zhang, Wenjie
Scrivo, Aurora
Fernández Carasa, Irene
Consiglio, Antonella
Aytés Meneses, Álvaro
Pujana Genestar, M. Ángel
Llebaria Soldevila, Amadeu
Antolin, Albert A.
author_role author
author2 Serra, Carme
Zhang, Wenjie
Scrivo, Aurora
Fernández Carasa, Irene
Consiglio, Antonella
Aytés Meneses, Álvaro
Pujana Genestar, M. Ángel
Llebaria Soldevila, Amadeu
Antolin, Albert A.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Medicaments antineoplàstics
Càncer de pròstata
Farmacologia
Metabòlits
Antineoplastic agents
Prostate cancer
Pharmacology
Metabolites
topic Medicaments antineoplàstics
Càncer de pròstata
Farmacologia
Metabòlits
Antineoplastic agents
Prostate cancer
Pharmacology
Metabolites
description The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polypharmacology of M324, the major metabolite of the PARP1 inhibitor rucaparib. We demonstrate that M324 displays unique PLK2 inhibition at clinical concentrations. This kinase activity could have implications for the efficacy and safety of rucaparib and therefore warrants further clinical investigation. Importantly, we identify synergy between the drug and the metabolite in prostate cancer models and a complete reduction of α-synuclein accumulation in Parkinson's disease models. These activities could be harnessed in the clinic or open new drug discovery opportunities. The study reported here highlights the importance of characterizing the activity of drug metabolites to comprehensively understand drug response in the clinic and exploit our current drug arsenal in precision medicine.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/215772
url https://hdl.handle.net/2445/215772
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.chembiol.2024.01.007
Cell Chemical Biology, 2024, vol. 31, num.5, p. 973-988
https://doi.org/10.1016/j.chembiol.2024.01.007
dc.rights.none.fl_str_mv cc-by (c) Hu, Huabin et al., 2024
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Hu, Huabin et al., 2024
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 21 p.
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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