Once in the body, medications, in addition to fulfilling their therapeutic function, are biochemically transformed by a metabolic mechanism, a process that facilitates their expulsion. This biotransformation leads to the gradual disappearance of the drug, which is converted into its metabolites. They, in turn, can reach high concentrations in the body and also exhibit biological activity, which may differ from the activity of the original drug. That is, the metabolites and the drug coexist in the body and can produce effects that are different from those achieved by using the individual molecules. This is the case Rucaparib, a drug used in chemotherapy for ovarian cancer, breast cancer and, more recently, prostate cancer, as well as its metabolite, the molecule M324. Rucaparib is part of a group of drugs designed to treat several types of cancer that involve changes in DNA repair. In particular, they are inhibitors PARP1 enzymeinvolved, in particular, in the process of correcting mutations in genetic material.
The study points to a new conceptual perspective in pharmacology.
Study conducted by researchers Albert A. Antolinbelonging Bellwitge Institute for Biomedical Research Oncobell Program (IDIBELL) and ProCure of the Catalan Institute of Oncology (ICO), as well as Amadeu Llebaria of the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) showed that rucaparib and its main metabolite M324 exhibit different activities. Published in Journal “Cell Chemical Biology”The work analyzed Rucaparib and M324, making a computational prediction of metabolite activity. The article describes the synthesis of M324 and its biological analysis, demonstrating that the drug and its metabolite have differential activity and act synergistically on several prostate cancer cell lines. And, surprisingly, M324 reduces protein accumulation α-synuclein (an important component of Lewy bodies), in neurons obtained from patients with Parkinson’s disease, a neurodegenerative disease characterized by movement disorders in which neurons do not produce enough of the neurotransmitter dopamine.
Medicines and their metabolic products can be used in personalized medicine
In particular, the synergy demonstrated between rucaparib and M324 in prostate cancer cell lines. may affect late-stage clinical trials this type of cancer. On the other hand, the fact that M324 is able to reduce the abnormal accumulation of alpha-synuclein in neurons derived from stem cells of a patient with Parkinson’s disease highlights the therapeutic potential of this metabolite and its possible pharmacological application for the treatment of this neurodegenerative disease. . Such results were obtained thanks to the cooperation of the IDIBELL and ICO groups under the leadership Mikel Angel Pujana, Alvaro Aites and group Antonella Consigliofrom IDIBELL and UB.
“Thanks to computational and experimental methods, we were able to comprehensively characterize the pharmacology of the M324 molecule for the first time,” says Antolin. recently received a Junior Leader Scholarship from the La Caixa Foundation.. The first author of the work, Huabing Hu, made a comprehensive prediction of the differential activity of the original drug and its product, which is expressed in different spectra of the phosphorylation pattern of cellular proteins. Carmen Serrafrom the MCS group IQAC-CSIC synthesized the metabolite M324, which allowed experimental confirmation in biological and cellular assays computational prediction. The findings may have implications for the clinical treatment of rucaparib and, in turn, open new avenues for drug discovery.
Drug metabolism may have potential therapeutic benefits
Thus, the study indicates a new conceptual view in pharmacology: which views drug metabolism not as an unwanted process that destroys and removes a therapeutic molecule from the body, but rather as a process that may have potential benefits from a therapeutic point of view. Indeed, the work highlights the importance of characterizing the activity of drug metabolites for a comprehensive understanding of their clinical response and its application in precision medicine.
Leading research center in the world
The Bellvitge Institute for Biomedical Research is a biomedical research center established in 2004. It involves the University Hospital of Bellvitge and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the Llobregat Hospital. Town Hall.
