Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease

2009 ◽  
Vol 70 (2) ◽  
pp. 125-144 ◽  
Author(s):  
Mary J. Savage ◽  
Diane E. Gingrich
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Kinase Inhibitor

scholarly journals Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview

2021 ◽  
Author(s):  
Agnieszka Zabłocka ◽  
Wioletta Kazana ◽  
Marta Sochocka ◽  
Bartłomiej Stańczykiewicz ◽  
Maria Janusz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Kinase Inhibitor ◽  
Fungal Infections ◽  
Neurological Diseases ◽  
Inverse Correlation ◽  
Biological Mechanisms ◽  
Age Related ◽  
Common Risk Factors

AbstractThe negative association between Alzheimer’s disease (AD) and cancer suggests that susceptibility to one disease may protect against the other. When biological mechanisms of AD and cancer and relationship between them are understood, the unsolved problem of both diseases which still touches the growing human population could be overcome. Actual information about biological mechanisms and common risk factors such as chronic inflammation, age-related metabolic deregulation, and family history is presented here. Common signaling pathways, e.g., p53, Wnt, role of Pin1, and microRNA, are discussed as well. Much attention is also paid to the potential impact of chronic viral, bacterial, and fungal infections that are responsible for the inflammatory pathway in AD and also play a key role to cancer development. New data about common mechanisms in etiopathology of cancer and neurological diseases suggests new therapeutic strategies. Among them, the use of nilotinib, tyrosine kinase inhibitor, protein kinase C, and bexarotene is the most promising.

Masitinib for the treatment of Alzheimer's disease

2021 ◽  
Vol 11 (4) ◽  
pp. 263-276
Author(s):  
Miren Ettcheto ◽  
Amanda Cano ◽  
Elena Sanchez-López ◽  
Ester Verdaguer ◽  
Jaume Folch ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Kinase Inhibitor ◽  
Phase Iii ◽  
Protein Signaling ◽  
Positive Effects ◽  
Activity Inhibition ◽  
Pharmacological Targets ◽  
Preclinical And Clinical Studies ◽  
Phase Iii Studies

The actual standard treatment for mild-to-moderately severe Alzheimer's disease only attacks its symptoms. Masitinib is a potent and selective phenylaminothiazole-type tyrosine kinase inhibitor which is currently in Phase III studies for the treatment of Alzheimer's disease (AD) with the aim of modifying its evolution and with multiple pharmacological targets such as inhibition of mast cells activity, inhibition of microglia activation, modulation of Aβ and Tau protein signaling pathway and prevention of synaptic damage. Here, we review the preclinical and clinical studies that investigated the administration of masitinib treatment in monotherapy in AD. All research studies revealed positive effects concerning the cognitive functions in AD and generally with good safety and tolerability.

Cell-dependent kinase inhibitor 2A and 2B genetic variability in patients with Alzheimer’s disease

2010 ◽  
Vol 258 (4) ◽  
pp. 704-705
Author(s):  
Francesca Cortini ◽  
Chiara Fenoglio ◽  
Eliana Venturelli ◽  
Chiara Villa ◽  
Francesca Clerici ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variability ◽  
Kinase Inhibitor

scholarly journals The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

2021 ◽  
Vol 22 (6) ◽  
pp. 3136
Author(s):  
Jacques Hugon ◽  
Claire Paquet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mitogen Activated Protein

Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.

scholarly journals Transcriptome Analysis of Cells Exposed to Actinomycin D and Nutlin-3a Reveals New Candidate p53-Target Genes and Indicates That CHIR-98014 Is an Important Inhibitor of p53 Activity

2021 ◽  
Vol 22 (20) ◽  
pp. 11072
Author(s):  
Barbara Łasut-Szyszka ◽  
Beata Małachowska ◽  
Agnieszka Gdowicz-Kłosok ◽  
Małgorzata Krześniak ◽  
Magdalena Głowala-Kosińska ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Innate Immunity ◽  
Target Genes ◽  
Actinomycin D ◽  
Kinase Inhibitor ◽  
A549 Cells ◽  
Rna Seq ◽  
Antiviral Genes ◽  
P53 Target Genes

Co-treatment with actinomycin D and nutlin-3a (A + N) strongly activates p53. Previously we reported that CHIR-98014 (GSK-3 kinase inhibitor), acting in cells exposed to A + N, prevents activation of TREM2-an innate immunity and p53-regulated gene associated with Alzheimer’s disease. In order to find novel candidate p53-target genes and genes regulated by CHIR-98014, we performed RNA-Seq of control A549 cells and the cells exposed to A + N, A + N with CHIR-98014 or to CHIR-98014. We validated the data for selected genes using RT-PCR and/or Western blotting. Using CRISPR/Cas9 technology we generated p53-deficient cells. These tools enabled us to identify dozens of candidate p53-regulated genes. We confirmed that p53 participates in upregulation of BLNK, APOE and IRF1. BLNK assists in activation of immune cells, APOE codes for apolipoprotein associated with Alzheimer’s disease and IRF1 is activated by interferon gamma and regulates expression of antiviral genes. CHIR-98014 prevented or inhibited the upregulation of a fraction of genes stimulated by A + N. Downregulation of GSK-3 did not mimic the activity of CHIR-98014. Our data generate the hypothesis, that an unidentified kinase inhibited by CHIR-98014, participates in modification of p53 and enables it to activate a subset of its target genes, e.g., the ones associated with innate immunity.

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