Efficacy of cyclin dependent kinase 4 inhibitors as potent neuroprotective agents against insults relevant to alzheimer's disease
Open accessAbstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure till today. Aberrant activation of cell cycle regulatory proteins is implicated in neurodegenerative diseases including AD. We and others have shown that Cyclin dependent kinase 4 (Cdk4) is activated in AD brain and is required for neuron death. In this study, we tested the efficiency of commercially available Cdk4 specific inhibitors as well as a small library of synthetic molecule inhibitors targeting Cdk4 as neuroprotective agents in cellular models of neuron death. We found that several of these inhibitors significantly protected neuronal cells against death induced by nerve growth factor (NGF) deprivation and oligomeric beta amyloid (Aβ) that are implicated in AD. These neuroprotective agents inhibit specifically Cdk4 kinase activity, loss of mitochondrial integrity, induction of pro-apoptotic protein Bim and caspase3 activation in response to NGF deprivation. The efficacies of commercial and synthesized inhibitors are comparable. The synthesized molecules are either phenanthrene based or naphthalene based and they are synthesized by using Pschorr reaction and Buchwald coupling respectively as one of the key steps. A number of molecules of both kinds block neurodegeneration effectively. Therefore, we propose that Cdk4 inhibition would be a therapeutic choice for ameliorating neurodegeneration in AD and these synthetic Cdk4 inhibitors could lead to development of effective drugs for AD.
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THN-fused C3-spirooxindoles should possess good druglikeness because THN and spirooxindole derivatives are privileged drug-like architectures.
“We started with THN54, 55, 56, 57, 58, 59, 60, 61 and spirooxindole derivatives62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 because they are privileged drug-like architectures, so the resulting THN-fused C3-spirooxindoles should possess good druglikeness (Fig. 2C).”
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References 47 · Cited by 38
Research works printed but not linked: 1
- [41]Greene LA, Liu DX, Troy CM, Biswas SC (2007) Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta 1772: 392– 401. 17229557 PMC1885990
- Authors
- Sanphui, P., Pramanik, S. K., Chatterjee, N., Moorthi, P., Banerji, B., & Biswas, S. C.
- Affiliations
- Indian Institute of Chemical Biology (IN)
- Corresponding author
- Banerji, Biswadip
- Biswas, Subhas Chandra
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-11
- Volume
- 8
- Issue
- 11
- Pages
- e78842
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3823981
- OpenAlex
- W1974075485
- Cited by
- 38
- References
- 47
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 9 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 4
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Greater South Information System
- Funders
- Department of Science and Technology, Ministry of Science and Technology, India
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- Alzheimer's disease, CDK4, CDK4 inhibitors, neuroprotection, neuronal cell death, nerve growth factor deprivation, mitochondrial integrity, building information modeling, caspase-3, phenanthrene derivatives, naphthalene derivatives, Pschorr reaction, small molecule synthesis, cell cycle dysregulation
- MeSH terms
- Bcl-2-Like Protein 11, Alzheimer Disease, Animals, Membrane Proteins, Neurons, Proto-Oncogene Proteins, PC12 Cells, Cell Death, Neuroprotective Agents, Nerve Growth Factor, Protein Kinase Inhibitors, Apoptosis Regulatory Proteins, Cyclin-Dependent Kinase 4, Rats, Caspase 3
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