New way to treat Parkinson’s disease inspired by an anti-cancer drug

2024-02-17 07:15:15

Once drugs enter the body, apart from performing their therapeutic function, they are biochemically transformed by the action of the metabolic machinery, a process that facilitates their expulsion. This biotransformation results in a gradual disappearance of the drug, which is converted into its metabolites. These, in turn, can reach high concentrations in the body and also show a biological activity that may be different from that of the original drug. That is, the metabolites and the drug coexist in the body, and can cause different effects than those obtained with the individual molecules.

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This is the case of Rucaparib, a drug used in chemotherapy for ovarian cancer, breast cancer and, more recently, prostate cancer, and its metabolite, the M324 molecule. Rucaparib is part of a group of drugs designed to treat several types of cancers that show alterations in DNA repair. Specifically, they are inhibitors of the PARP1 enzyme, involved precisely in the process of repairing mutations in the genetic material.

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A study carried out by a team made up of, among others, Albert A. Antolin, from the Oncobell program of the Bellvitge Biomedical Research Institute (IDIBELL) and ProCure from the Catalan Institute of Oncology (ICO), Amadeu Llebaria, from the of Advanced Chemistry of Catalonia (IQAC) attached to the Higher Scientific Research Council (CSIC) in Spain, and Huabin Hu, of the Cancer Research Institute in London, United Kingdom, has shown that Rucaparib and its main M324 metabolite exhibit differential activities.

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The researchers have analyzed Rucaparib and M324, making a computational prediction of the metabolite’s activity. They have described the synthesis of M324 and performed a biological assay, demonstrating that the drug and its metabolite have differentiated activities and act synergistically in some prostate cancer cell lines.

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And that, surprisingly, M324 reduces the accumulation of the protein alpha-synuclein (an important component of Lewy bodies), in neurons derived from Parkinson’s patients, a neurodegenerative disease characterized by a movement disorder, and in which Neurons do not produce sufficient amounts of the neurotransmitter dopamine.

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Specifically, the synergy demonstrated between Rucaparib and M324 in prostate cancer cell lines could have an impact in clinical trials for advanced stages of this type of cancer. On the other hand, the fact that M324 is capable of reducing the abnormal accumulation of α-synuclein in neurons derived from stem cells of a Parkinson’s patient, highlights the therapeutic potential of this metabolite and its possible pharmacological application for the treatment of this disease. These results have been obtained thanks to the collaboration of the IDIBELL and ICO groups led by Miquel Àngel Pujana, à lvaro Aytés and the group of Antonella Consiglio, IDIBELL and the University of Barcelona (UB).

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Parkinson’s is a disease in which neurons do not produce sufficient amounts of the neurotransmitter dopamine. (Illustration: Amazings / NCYT)

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Researchers have used computational and experimental methods to comprehensively characterize, and for the first time, the pharmacology of the M324 molecule. The first author of the work, Huabin Hu, has made an exhaustive prediction of the differential activity of the original drug and its product, which translates into different spectra of the phosphorylation pattern of cellular proteins.

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Carme Serra, from the MCS group at IQAC, has synthesized the metabolite M324, which has made it possible to experimentally verify, in biological and cellular assays, the computational prediction. The results obtained could have implications for clinical treatment with Rucaparib and, in turn, open new opportunities for drug discovery.

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In summary, the study points towards a new conceptual perspective in pharmacology: one that considers drug metabolism not as an undesirable process that degrades and eliminates the therapeutic molecule from the organism, but rather as one that may have potential advantages from the therapeutic point of view.

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Indeed, the work highlights the importance of characterizing the activity of drug metabolites to comprehensively understand their clinical response and apply it in precision medicine.

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The study is titled “Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite†. And it’s been published in the academic journal Cell Chemical Biology. (Source: IQAC / CSIC)

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