Radotinib and the Therapeutic Potential of c-Abl Inhibitors in Parkinson’s Disease

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Oxidative Stress and Its Role in Parkinson’s Disease

Oxidative stress, defined as an imbalance between free radical production and antioxidant defenses, is widely implicated in the pathogenesis of Parkinson’s disease (PD). This imbalance contributes to cellular dysfunction and neuronal death, manifesting as symptoms such as fatigue, memory decline, headache, and muscular pain. Post-mortem studies of PD brains consistently demonstrate elevated oxidative stress within key regions such as the substantia nigra and striatum, suggesting its central role in disease progression.

The non-receptor tyrosine kinase c-Abl is activated under oxidative stress conditions and has emerged as a critical mediator of neurodegeneration. Evidence shows increased c-Abl activity in PD brains, linking this pathway to α-synuclein pathology and dopaminergic neuronal loss.

c-Abl and α-Synuclein Pathology

Preclinical models demonstrate that suppression of c-Abl activity can protect dopaminergic neurons and limit α-synuclein aggregation. The pathogenic mechanism involves phosphorylation of α-synuclein at tyrosine-39, which promotes protein aggregation while simultaneously disrupting its physiological role. Studies suggest that c-Abl activation exacerbates cellular stress and accelerates neurodegenerative processes. Conversely, inhibition of this kinase improves neuronal survival, motor function, and cognitive outcomes in vivo.

Radotinib as a Candidate Therapy

Radotinib hydrochloride, an orally available c-Abl inhibitor with favorable pharmacokinetic properties and demonstrated ability to cross the blood–brain barrier, has shown encouraging results in experimental PD models. Administration of Radotinib in α-synuclein preformed fibril (PFF) mouse models reduces protein aggregation and protects dopaminergic neurons within the substantia nigra. These effects are associated with significant improvements in both motor and cognitive performance.

Beyond reducing α-synuclein pathology, Radotinib exhibits additional neuroprotective effects. It suppresses chronic neuroinflammation, a well-documented contributor to PD and Alzheimer’s disease progression. Furthermore, Radotinib restores mitochondrial respiratory function, thereby enhancing cellular resilience and survival.

Comparison with Other c-Abl Inhibitors

Several c-Abl inhibitors are under investigation for PD therapy, including Radotinib, Vodobatinib (K0706), IkT-148009, and Nilotinib.

• Vodobatinib (K0706): Currently undergoing clinical evaluation in early-stage PD patients (PROSEEK trial). It demonstrates favorable safety and tolerability with reported side effects limited to gastrointestinal disturbances such as diarrhea and vomiting. Vodobatinib effectively reduces α-synuclein aggregation and supports cognitive and motor function in preclinical models.
• Nilotinib: While initially promising in animal studies, its limited ability to cross the blood–brain barrier has restricted its efficacy in clinical settings.
• IkT-148009: Another emerging compound with strong brain penetration, currently being evaluated for therapeutic relevance.

Overall, Radotinib and Vodobatinib appear most promising, as they not only cross the blood–brain barrier effectively but also demonstrate strong neuroprotective potential with acceptable safety profiles.

Clinical Perspective

The inhibition of c-Abl represents a compelling therapeutic approach in PD. By preventing α-synuclein aggregation, reducing neuroinflammation, and preserving mitochondrial function, c-Abl inhibitors may address both the underlying pathology and symptomatic burden of the disease. Current clinical trials for Radotinib and Vodobatinib will be pivotal in determining their long-term safety and efficacy.

While Nilotinib demonstrated mechanistic proof-of-concept, its limited brain penetration highlights the importance of optimizing pharmacological properties in drug design. Radotinib and Vodobatinib, with their favorable bioavailability and ability to cross the blood–brain barrier, stand out as the most clinically relevant candidates.

REFERENCES

1. Karuppagounder, S. S., Brahmachari, S., Lee, Y., Dawson, V. L., Dawson, T. M., & Ko, H. S. (2014). The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease.Scientific reports, 4(1), 4874.
2. Kwon, S. H., Kim, S., Park, A. Y., Lee, S., Gadhe, C. G., Seo, B. A., … & Ko, H. S. (2021). A novel, selective c-Abl inhibitor, compound 5, prevents neurodegeneration in Parkinson’s disease.Journal of medicinal chemistry, 64(20), 15091-15110.
3. Lee, S., Kim, S., Park, Y. J., Yun, S. P., Kwon, S. H., Kim, D., … & Ko, H. S. (2018). The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson’s disease mouse model.Human molecular genetics, 27(13), 2344-2356. 
4. Simuni, T., & Merchant, K. (2023). A novel brain penetrant c-Abl tyrosine kinase inhibitor: Paving a path forward to success in disease modification in Parkinson’s disease.Parkinsonism & Related Disorders, 108.
5. Simuni, T., Fiske, B., Merchant, K., Coffey, C. S., Klingner, E., Caspell-Garcia, C., … & LeDoux, M. (2021). Efficacy of nilotinib in patients with moderately advanced Parkinson disease: a randomized clinical trial.JAMA neurology, 78(3), 312-320.
6. Walsh, R. R., Damle, N. K., Mandhane, S., Piccoli, S. P., Talluri, R. S., Love, D., … & Hurko, O. (2023). Plasma and cerebrospinal fluid pharmacokinetics of vodobatinib, a neuroprotective c-Abl tyrosine kinase inhibitor for the treatment of Parkinson’s disease.Parkinsonism & Related Disorders, 108, 105281.
7. Walsh, R. R., Piccoli, S. P., Talluri, R. S., Mandhane, S., Love, D., Hurko, O., … & Damle, N. (2023). Vodobatinib, a potent, orally bioavailable brain-penetrating inhibitor of c-Abl as a potential neuroprotective agent for treatment of Parkinson disease.Parkinsonism & Related Disorders, 113.
8. Werner, M. H., & Olanow, C. W. (2022). Parkinson’s disease modification through Abl kinase inhibition: an opportunity.Movement Disorders, 37(1)