Rucaparib and its major metabolite exhibit differential biological activity and synergy

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Once they enter the body, drugs, in addition to carrying out their therapeutic function, are biochemically transformed by the action of metabolic machinery, a process that facilitates their elimination. This biotransformation results in the 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 can be different from the parent drug. That is, metabolites and drugs coexist in the body and can produce effects different from those obtained with separate molecules. This is the case with 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 various types of cancer that show alterations in DNA repair. In particular, they are inhibitors of the PARP1 enzyme, precisely involved in the process of repairing mutations in genetic material.

Oncobel Program of Belvit Biomedical Research Institute (IDIBEL) and ProCure of the Catalan Institute of Oncology (ICO) and researcher Albert A. A study led by Antolin. CSIC), showed that Rucaparib and its major metabolite M324 exhibited differential activity. Published in Journal Cell Chemical Biology, the paper performed a computational prediction of metabolite activity, analyzing Rucaparib and M324. The article describes the synthesis of M324 and its biological testing, demonstrating that the drug and its metabolites have distinct activities and act synergistically in some prostate cancer cell lines. And it, surprisingly, M324 reduced the accumulation of the protein α-synuclein (an important component of Lewy bodies) in neurons obtained from Parkinson’s patients, a neurodegenerative disease characterized by a movement disorder and in which the neurons do not produce enough. The neurotransmitter dopamine.

In particular, the demonstrated synergy between rucaparib and M324 in prostate cancer cell lines may have implications for clinical trials for advanced stages of this type of cancer. On the other hand, M324 is able to reduce the abnormal accumulation of α-synuclein in Parkinson patient stem cell-derived neurons, highlighting the therapeutic potential of this metabolite and its potential pharmacological application for the treatment of this neurodegenerative disease. .. These results were obtained thanks to the collaboration of the IDIBELL and ICO groups led by Mikel Angel Pujana and Alvaro Ites and the Antonella Consiglio group from IDIBELL and UB.

The researchers used computational and experimental methods to characterize extensively, and for the first time, the pharmacology of the M324 molecule. The work’s first author, Huabin Hu, made a complete prediction of the differential activity of the parent drug and its products, which translates into a different spectrum of cellular protein phosphorylation patterns. Karme Sera, from the MCS group at IQAC-CSIC, synthesized metabolite M324, which allowed experimental verification of computational predictions in biological and cellular assays. The results obtained may have implications for clinical treatment with rucaparib and, consequently, may open new opportunities for drug discovery.

In short, the study points to a new conceptual approach in pharmacology: one that considers drug metabolism not as an unwanted process that degrades and eliminates therapeutic molecules from the body, but as one that can have potential benefits from a therapeutic perspective. . Indeed, the work highlights the importance of characterizing drug metabolite activity to comprehensively understand their clinical response and apply it to precision medicine.

Source:

Journal Reference:

Hu, H., etc. (2024). Differential biological activity and synergy between the PARP inhibitor Rucaparib and its major metabolites. Cell Chemical Biology. doi.org/10.1016/j.chembiol.2024.01.007.



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