Efficacy of cyclin dependent kinase 4 inhibitors as potent neuroprotective agents against insults relevant to Alzheimer's disease.
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.
Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Priyankar
P
Sanphui
Sumit Kumar
SK
Pramanik
Nandini
N
Chatterjee
Ponnusamy
P
Moorthi
Biswadip
B
Banerji
Subhas Chandra
SC
Biswas
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020932:Nerve Growth Factor; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; C505410:Casp3 protein, rat; D053148:Caspase 3