Objective: Preclinical assessment of K0706, a potent c-Abl inhibitor, as a neuroprotective disease modifying agent for the treatment of Parkinson’s disease (PD) related neurodegeneration using various in vitro and in vivo models, and brain pharmacokinetics.

Background: C-Abelson (cAbl) is a non-receptor protein tyrosine kinase, broadly expressed in various tissues including cells within the CNS. cABL is activated in response to a multitude of biochemical insults and has been shown to contribute to neuronal death underlying various neurodegenerative conditions including PD. Hence, inhibition of cABL may be therapeutically beneficial in preventing or slowing down neurodegeneration underlying PD.

Method: In vitro potency and selectivity of K0706 against a panel of protein kinases was assessed. Modulation of parkin activity, autophagic flux and α-synuclein (αSYN) metabolism were studied in different cell lines including human iPSC-derived neurons. In vivo, brain, plasma and CSF pharmacokinetic assessments of K0706 were done in rodents and non-human primates (NHP).  K0706 was also evaluated in rodent models of MPTP-mediated or alpha synuclein-mediated dopaminergic neurodegeneration. In C57BL/6J mice, neurodegeneration was induced by intra-peritoneal administration of MPTP. In SD rats, the disease state was induced by administration of AAV1/2 encoding human A53T αSYN into the substantia nigra.

Results: K0706 inhibited preferentially, with a sub-nanomolar potency, protein kinase activity of both cABL (ABL-1) and cARG (ABL-2). In iPSC-derived neurons, K0706 increased autophagic flux without influencing E3 ligase activity of parkin, or the overall metabolism of αSYN. K0706 exhibited an appreciable blood–brain barrier penetration with a good Kp,brain and Kp,CSF in mice, rats and NHPs.  In C57BL/6J mice, K0706 rescued TH positive neurons against MPTP insult. In rat model of AAV1/2-A53T αSYN pathology, K0706 showed protection of nigral and striatal TH.

Conclusion: K0706 is a potent and selective brain penetrant c-Abl inhibitor with disease modifying capability. K0706 showed promising disease modifying activity in animal models of dopaminergic neurodegeneration and synucleinopathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/k0706-a-potent-orally-bioavailable-brain-penetrating-selective-inhibitor-of-cabl-protein-tyrosine-kinase-exhibits-neuroprotective-activity-in-preclinical-models-of-parkinsons-disease/