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
  • 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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