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 pot..., Study Design: The in-silico design method known as RAMPTM was applied to design and develop inhibitors of the non-receptor Abelson tyrosine kinases c-Abl1 (c-Abl) and c-Abl2/Arg as described in Supplementary Materials. Three candidate molecules emerged from RAMPTM that were first screened in a modification of the pre-exposure prophylaxis MPTP model of Parkinsonism and subsequently compared to the commercial inhibitors nilotinib and dasatinib in the same model. Following the selection of one candidate inhibitor, IkT-148009, a model of slowly progressive inherited disease using the clinical mutation A53T of a-synuclein and a model of slowly progressive sporadic disease using pre-formed fibrils (PFFs) were utilized to evaluate the therapeutic activity of daily oral administration of IkT-148009 as a modifier of neurodegeneration, markers of neuroinflammation and a-synuclein pathology. The number of animals utilized in each sub-study described was not determined by power analysis, rather, wa..., Zen lite
Graphpad Prism
ImageJ
Adobe Iliustrator