Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Dec 18;21(24):9677.
doi: 10.3390/ijms21249677.

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer's Diseases

Stephanie Cristine Hepp Rehfeldt  1 , Fernanda Majolo  1   2 , Márcia Inês Goettert  1 , Stefan Laufer  3
Affiliations
Review

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer's Diseases

Stephanie Cristine Hepp Rehfeldt et al. Int J Mol Sci. .

Abstract

Alzheimer's Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.

Keywords: brain diseases; c-Jun N-terminal kinase (JNK); kinase inhibitors; therapeutic targets.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results

Figures

Figure 1
Figure 1
Schematic representation of the typical mitogen-activated protein kinases (MAPK) pathway, composed of three levels (three-tier module) and four subfamilies: extracellular signal-regulated kinases (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK), and ERK5. Each subfamily regulates different phenotypes. While the canonical ERK subfamily (ERK1/2) responds to mitotic stimuli and controls cellular differentiation and proliferation, JNK and p38 are activated by stressor stimuli and are involved in apoptosis. Since the ERK5 subfamily responds to both mitotic and stressor stimuli, being associated with cell survival, it is presented in a special subfamily.
Figure 2
Figure 2
Schematic representation of JNK role in intrinsic and extrinsic apoptosis.
Figure 3
Figure 3
Two-dimensional structure of JNK3. Key structure elements are colored as shown in legend. Figure generated with Protter.
Figure 4
Figure 4
(A–D) Structural superposition of JNK3 (PDB code: 3OY1, chain A, represented in red) and ERK1 (PDB code: 2ZOQ, chain A, represented in green); (E–H) Structural superposition of JNK3 (PDB code: 3OY1, chain A, represented in red) and p38α (PDB code: 1A9U, chain A, represented in green). Figure generated by iPBA.
Figure 4
Figure 4
(A–D) Structural superposition of JNK3 (PDB code: 3OY1, chain A, represented in red) and ERK1 (PDB code: 2ZOQ, chain A, represented in green); (E–H) Structural superposition of JNK3 (PDB code: 3OY1, chain A, represented in red) and p38α (PDB code: 1A9U, chain A, represented in green). Figure generated by iPBA.
Figure 5
Figure 5
(A) Overview of the three-dimensional structure of the JNK3 interacting with its ligand (PDB code: 3OY1); (B) 2D protein-ligand interaction plot for 3OY1, emphasizing the interactions between the ligand and the residue Met149. The hydrogen bond (at atom level) is shown in dashed lines. Amino acids that do not interact with the ligand via hydrogen bond are shown in green. Water molecules are not shown. Plot automatically generated by ProteinsPlus using the PoseView tool based on the 2Ddraw library.
Figure 6
Figure 6
Schematic representation of the mechanism of action of JNK inhibitors.
Figure 7
Figure 7
Summary of small molecules of JNK inhibitors used in neurological models that could be used as approaches to develop new Alzheimer’s disease (AD) therapeutics [157,185,186,187,188,189,190,191,192,213,214,215,216,217].
Figure 7
Figure 7
Summary of small molecules of JNK inhibitors used in neurological models that could be used as approaches to develop new Alzheimer’s disease (AD) therapeutics [157,185,186,187,188,189,190,191,192,213,214,215,216,217].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Small D.H., Cappai R. Alois Alzheimer and Alzheimer’s disease: A centennial perspective. J. Neurochem. 2006;99:708–710. doi: 10.1111/j.1471-4159.2006.04212.x. - DOI - PubMed
    1. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichttliche Medizin. 1907;64:146–148.
    1. Nichols E., Szoeke C.E.I., Vollset S.E., Abbasi N., Abd-Allah F., Abdela J., Aichour M.T.E., Akinyemi R.O., Alahdab F., Asgedom S.W., et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:88–106. doi: 10.1016/S1474-4422(18)30403-4. - DOI - PMC - PubMed
    1. Alzheimer’s Association Alzheimer’s disease facts and figures. Alzheimer’s Dementia. 2017;13:325–373. doi: 10.1016/j.jalz.2017.02.001. - DOI - PubMed
    1. Alzheimer’s Association Alzheimer’s Disease Facts and Figures. Alzheimer’s Dementia. 2019;15:321–387. doi: 10.1016/j.jalz.2019.01.010. - DOI

MeSH terms

Substances