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A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease
J Med Chem. 2021 Sep 28. doi: 10.1021/acs.jmedchem.1c01022.
Seung-Hwan Kwon 1 2, Sangjune Kim 1 2 3, A Yeong Park 4, Saebom Lee 1 2, Changdev Gorakshnath Gadhe 4, Bo Am Seo 1 2, Jong-Sung Park 5, Suyeon Jo 4, Yumin Oh 5 6, Sin Ho Kweon 1 2, Shi-Xun Ma 1 2, Wonjoong R Kim 1 2, Misoon Kim 4, Hyeongjun Kim 4, Jae Eun Kim 4, Seulki Lee 5 6, Jinhwa Lee 4, Han Seok Ko 1 2
Abstract:
...The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.
PMID: 34583507
Tags: alpha-synuclein, c-Abl, Compound 5, mice, parkinson's