2. Academic Validation
  3. A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease

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

  • J Med Chem. 2021 Oct 28;64(20):15091-15110. 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
Affiliations

Affiliations

  • 1 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
  • 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
  • 3 Department of Biology, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
  • 4 1ST Biotherapeutics, Inc., 240 Pangyoyeok-ro A-313, Bundang-gu, Seongnam-si, Gyeonggi-do 13493, Republic of Korea.
  • 5 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
  • 6 Neuraly, Inc., Gaithersburg, Maryland 20878, United States.
PMID: 34583507 DOI: 10.1021/acs.jmedchem.1c01022
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.

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