A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease

Seung Hwan Kwon, Sangjune Kim, A. Yeong Park, Saebom Lee, Changdev Gorakshnath Gadhe, Bo Am Seo, Jong Sung Park, Suyeon Jo, Yumin Oh, Sin Ho Kweon, Shi Xun Ma, Wonjoong R. Kim, Misoon Kim, Hyeongjun Kim, Jae Eun Kim, Seulki Lee, Jinhwa Lee, Han Seok Ko

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. 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.

Original languageEnglish (US)
JournalJournal of medicinal chemistry
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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