The c-Abl inhibitor IkT-148009 therapeutically suppresses neurodegeneration in models of heritable and sporadic Parkinson’s Disease

Parkinson’s Disease (PD) is the second most prevalent neurodegenerative
disease of the central nervous system, with an estimated 5,000,000 cases
worldwide. PD pathology is characterized by the accumulation of
misfolded a-synuclein, which is thought to play a critical role in the
etiopathogenesis of the disease. Animal models of PD suggest that
activation of the Abelson Tyrosine Kinase, or c-Abl, plays an essential
role in the initiation and progression of a-synuclein pathology and
initiates processes leading to the degeneration of dopaminergic and
non-dopaminergic neurons. Given the essential role of c-Abl in the
disease, a proprietary c-Abl inhibitor library was developed to identify
potent, orally bioavailable c-Abl inhibitors capable of crossing the
blood-brain barrier based on pre-defined characteristics, leading to the
discovery of IkT-148009. IkT-148009 is a selective, potent,
brain-penetrant c-Abl inhibitor with a favorable toxicology profile that
was analyzed for therapeutic potential in animal models of slowly
progressive, a-synuclein-dependent disease. In models of both inherited
and sporadic Parkinson’s disease in the mouse, IkT-148009 suppressed c-Abl
activation to baseline and substantially protected neurons from
degeneration when administered therapeutically by once daily oral gavage
beginning four weeks after disease initiation. Recovery of normal
behavioral function in diseased mice occurred within 8 weeks of initiating
treatment and occurred concomitantly with a substantial reduction of
a-synuclein pathology in the brain. These disease-modifying outcomes in
mice suggest IkT-148009 has the potential to be a disease-modifying
therapy in human disease.