The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease.

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Parkinson's disease is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. Parkinson disease pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease.

Animal models of Parkinson disease suggest that activation of Abelson tyrosine kinase plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons.

Four drugs, nilotinib, dasatinib, bosutinib and ponatinib are src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia. Given the potential role of c-Abl in Parkinson disease, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009.

IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent Parkinson disease.

In mouse models of both inherited and sporadic Parkinson disease, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation.

Recovery of motor function in Parkinson disease mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in Parkinson disease.

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