Objective: Here we synthesized a novel c-KIT/c-Abl  inhibitor BK40196 and investigated its effects on alpha-synuclein, neuro-inflammation , dopamine  and behavior in A53T mice.

Background: Inhibition of Tyrosine kinases (TKs) has been explored as a potential strategy for treating neurodegenerative diseases including Parkinson Disease (PD).  The activation of tyrosine kinase c-KIT leads to the phosphorylation of a serial of downstream substrates which involved in PD’s pathophysiological mechanisms such as neuro-inflammation, synaptic dysfunction and autophagy.

Method: Pharmacodynamics effects of BK40196 on behavior, protein levels and microglial activity in vivo.

Results: BK40196  is a c-KIT and c-Abl inhibitor and significantly reduces the levels of alpha-synuclein, increases tyrosine hydroxylase positive (TH+) neurons in substantia nigra (SN) and attenuates cell loss while improving motor functions in A53T mice. BK40196 is a dopamine receptor 1 agonist 1. BK40196 reduces microglial activity/the levels of brain tryptase in parallel with activation of D1 receptor.

Conclusion: BK40196 inhibits c-Kit/c-Abl and may play an important role in activation of dopamine 1 receptor, central immunity via microglia and induces anti-inflammation and protein clearance that are mutually beneficial to alleviate neurodegenerative pathology. BK40196 is a potential candidate for the treatment of human synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-c-kit-c-abl-inhibitor-bk40196-alleviates-neurodegenerative-pathology-and-improves-behavioral-performance-in-a53t-mice/