From time to time, scientists give us good news when they discover that a drug that was originally developed to treat a certain disease is also useful in relieving the symptoms of a different disease, or even curing it. This is what has now happened with the drug Rucaparib, which is used in chemotherapy for ovarian cancer, breast cancer and, more recently, prostate cancer, and which has been proven to have potential as a treatment for Parkinson’s.
The study has been led by researchers Albert A. Antolin, from the Oncobell program of the Bellvitge Biomedical Research Institute (IDIBELL) and ProCure of the Catalan Institute of Oncology (ICO), and Amadeu Llebaria, from the Institute of Advanced Chemistry of Catalonia (IQAC). -CSIC), and has shown that Rucaparib and its main metabolite, the M324 molecule, exhibit differential activities.
Researchers have explained that when drugs are introduced into the body, in addition to performing their therapeutic function, they are biochemically transformed by the action of the metabolic machinery, and that this process facilitates their expulsion. The result of this biotransformation is 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 effects different from those obtained with the individual molecules.”
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, which is precisely involved in the process of repairing mutations in the genetic material.
Drug metabolites could be used in precision medicine
The researchers have analyzed Rucaparib and M324, making a computational prediction of the metabolite’s activity. The article published in the journal Cell Chemical Biology describes the synthesis of M324 and its biological assay, demonstrating that the drug and its metabolite have differentiated activities and act synergistically in some prostate cancer cell lines.
They also found that, surprisingly, M324 reduces the accumulation of the protein α-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.
Specifically, the synergy demonstrated between Rucaparib and M324 in prostate cancer cell lines could have an impact on 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, demonstrates the therapeutic potential of this metabolite and its possible pharmacological application for the treatment of this disease. .
Rucaparib’s M324 molecule reduces the accumulation of the protein α-synuclein (an important component of Lewy bodies) in neurons derived from Parkinson’s patients
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.
Carme Serra, from the MCS group at IQAC-CSIC, has synthesized the metabolite M324, which has allowed experimental verification, in biological and cellular assays, of the computational prediction. The results obtained could have implications for clinical treatment with Rucaparib and, in turn, open new opportunities for drug discovery.
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 body, but rather as one that can have potential advantages from a therapeutic point of view. The work highlights the importance of characterizing the activity of drug metabolites to comprehensively understand their clinical response and apply it in precision medicine.
Source: Higher Council for Scientific Research (CSIC)
