Metabolite of cancer medication shows promise for Parkinson’s

M324 reduces abnormal alpha-synuclein clumps in patient-derived nerve cells

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by Andrea Lobo |

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A metabolite called M324 of the cancer medicine rucaparib is able to reduce the abnormal accumulation of alpha-synuclein protein in nerve cells derived from people with Parkinson’s disease, showing its potential for treating the neurodegenerative disorder, according to a new study.

Metabolites are molecules that result from the biochemical transformation of medicines inside the body. When a medicine is metabolized, it gradually disappears, and its metabolites accumulate and may have a different biological activity than the original therapy.

The study, “Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite,” was published in Cell Chemical Biology.

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Parkinson’s disease is caused by the progressive dysfunction and death of the nerve cells, called dopaminergic neurons, responsible for producing dopamine in the brain. Dopamine is a neurotransmitter, a signaling molecule neurons use to communicate, that is important for the control of voluntary movements.

Although the reasons why these neurons die are not fully known, the accumulation of toxic forms of the protein alpha-synuclein into clumps called Lewy bodies is thought to play a key role.

Now, a team of researchers in Spain has shown M324, the major metabolite of rucaparib (sold as Rubraca), was able to reduce the accumulation of alpha-synuclein in dopaminergic neurons derived from a Parkinson’s patient.

Rucaparib approved for ovarian, prostate cancers

Rucaparib is a medication for certain types of cancer, including ovarian and prostate. It belongs to a class of drugs known as PARP inhibitors. PARP is an enzyme involved in repairing damaged DNA in cells. In cancers with certain genetic mutations, inhibiting PARP can interfere with the ability of cancer cells to repair DNA damage, ultimately leading to their death.

In the study, researchers used computational methods to predict the biological activity of rucaparib and of M324 and were able to characterize the pharmacological activity of the metabolite. They were able to demonstrate that the medicine and its metabolite have differentiated activities.

Specifically, they found M324 could modulate several unique kinases, different from those inhibited by rucaparib. Kinases are enzymes that add a phosphate ion (phosphorylation) to other molecules, including proteins, thereby regulating their activity.

Rucaparib strongly inhibited GSK3B only, which is an enzyme that plays a role in various cellular processes. However, M324 also strongly inhibited PLK2, an enzyme known to phosphorylate alpha-synuclein, which is the primary form of the protein found in Lewy bodies. The effect was observed at clinically achievable concentrations.

This prompted the researchers to test M324 in a disease-relevant and well-characterized human cell model of Parkinson’s disease. The model is based on the differentiation of dopaminergic neurons from induced pluripotent stem cells (iPSCs) derived from Parkinson’s patients. iPSCs are stem cells generated from mature cells that can give rise to different cell types, including neurons.

The researchers used cells derived from a patient carrying the G2019S mutation in the LRRK2 gene, one of the most common mutations linked to Parkinson’s disease and is implicated in about 4% of familial cases and 1% of sporadic cases of the disease.

After one month growing in dishes under laboratory conditions, 60% of the patient-derived dopaminergic neurons exhibited an abnormal accumulation of alpha-synuclein. On the other hand, 20% of dopaminergic neurons derived from iPSCs of a healthy donor had the protein clumps.

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Adding M324 to neurons reduced proportion with alpha-synuclein clumps

Adding M324 to these neurons significantly reduced the proportion of nerve cells with an accumulation of alpha-synuclein, similar to the levels seen in healthy neurons. The researchers noted this was not accompanied by any sign of cellular toxicity.

“Overall, we can confirm a remarkable phenotype of the M324 as a single agent that contradicts the current vision of this metabolite as an inactive compound and opens exciting repurposing and drug discovery opportunities in [Parkinson’s disease],” the researchers wrote.

This study also “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,” they added.