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2024-02-08

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cc-by (c) Hu, Huabin et al., 2024
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215772

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

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https://doi.org/10.1016/j.chembiol.2024.01.007

Resum

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.

Matèries

Medicaments antineoplàstics, Càncer de pròstata, Farmacologia, Metabòlits

Matèries (anglès)

Antineoplastic agents, Prostate cancer, Pharmacology, Metabolites

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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.. Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite. _Cell Chemical Biology_. 2024. Vol. 31, núm. 5, pàgs. 973-988. [consulta: 26 de febrer de 2026]. ISSN: 2451-9456. [Disponible a: https://hdl.handle.net/2445/215772]

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