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

doi:10.1021/acs.jmedchem.1c01022

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

School of Medicine

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	15091-15110
Number of pages	20
Journal	Journal of medicinal chemistry
Volume	64
Issue number	20
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01022
State	Published - Oct 28 2021

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c01022

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Kwon, S. H., Kim, S., Park, A. Y., Lee, S., Gadhe, C. G., Seo, B. A., Park, J. S., Jo, S., Oh, Y., Kweon, S. H., Ma, S. X., Kim, W. R., Kim, M., Kim, H., Kim, J. E., Lee, S., Lee, J., & Ko, H. S. (2021). A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease. Journal of medicinal chemistry, 64(20), 15091-15110. https://doi.org/10.1021/acs.jmedchem.1c01022

Kwon, SH, Kim, S, Park, AY, Lee, S, Gadhe, CG, Seo, BA, Park, JS, Jo, S, Oh, Y, Kweon, SH, Ma, SX, Kim, WR, Kim, M, Kim, H, Kim, JE, Lee, S, Lee, J & Ko, HS 2021, 'A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease', Journal of medicinal chemistry, vol. 64, no. 20, pp. 15091-15110. https://doi.org/10.1021/acs.jmedchem.1c01022

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

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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AU - Kwon, Seung Hwan

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AU - Park, A. Yeong

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AU - Gadhe, Changdev Gorakshnath

AU - Seo, Bo Am

AU - Park, Jong Sung

AU - Jo, Suyeon

AU - Oh, Yumin

AU - Kweon, Sin Ho

AU - Ma, Shi Xun

AU - Kim, Wonjoong R.

AU - Kim, Misoon

AU - Kim, Hyeongjun

AU - Kim, Jae Eun

AU - Lee, Seulki

AU - Lee, Jinhwa

AU - Ko, Han Seok

PY - 2021/10/28

Y1 - 2021/10/28

N2 - 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.

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

Abstract

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