Identification and neuroprotective evaluation of a potential c-Jun N-terminal kinase 3 inhibitor through structure-based virtual screening and in-vitro assay

Rajan, Ravi Kumar; Ramanathan, Meena

doi:10.1007/s10822-020-00297-y

Cited by 9 publications

(9 citation statements)

References 40 publications

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“…Finally, there are also several chemical compounds identified with in-silico analysis and tested against AD neurodegeneration [ 150 ] and hypoxic insults [ 151 ], highlighting the potential of the specific inhibition of JNK3 in the brain.…”

Section: Tuning Jnk3 Pathway By Using Jip-1 and β-Arrestin-2mentioning

confidence: 99%

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Musi

Agrò

Santarella

et al. 2020

Cells

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The c-Jun N-terminal kinase 3 (JNK3) is the JNK isoform mainly expressed in the brain. It is the most responsive to many stress stimuli in the central nervous system from ischemia to Aβ oligomers toxicity. JNK3 activity is spatial and temporal organized by its scaffold protein, in particular JIP-1 and β-arrestin-2, which play a crucial role in regulating different cellular functions in different cellular districts. Extensive evidence has highlighted the possibility of exploiting these adaptors to interfere with JNK3 signaling in order to block its action. JNK plays a key role in the first neurodegenerative event, the perturbation of physiological synapse structure and function, known as synaptic dysfunction. Importantly, this is a common mechanism in many different brain pathologies. Synaptic dysfunction and spine loss have been reported to be pharmacologically reversible, opening new therapeutic directions in brain diseases. Being JNK3-detectable at the peripheral level, it could be used as a disease biomarker with the ultimate aim of allowing an early diagnosis of neurodegenerative and neurodevelopment diseases in a still prodromal phase.

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Section: Tuning Jnk3 Pathway By Using Jip-1 and β-Arrestin-2mentioning

confidence: 99%

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Musi

Agrò

Santarella

et al. 2020

Cells

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“…2.4.3 | Dual acridine orange/ethidium bromide (AO/EB) fluorescence staining Cells were cultured in DMEM/F12 medium supplemented with 10% FBS in 24 well plates. Cells were differentiated using RA, as previously described (Rajan & Ramanathan, 2020). Cells were pre-treated with different doses (1, 10, 30, 50, and 100 μM) of the PCT molecule followed by ischemic induction and reperfusion for 24 h. After the treatment period, dual fluorescent staining was performed using 100 μg/ mL AO and 100 μg/mL EtBr (Liu et al, 2015).…”

Section: Neuroprotective and Cytotoxic Evaluationmentioning

confidence: 99%

Piceatannol selectively inhibited the JNK3 enzyme and augmented apoptosis through inhibition of Bcl‐2/Cyt‐c/caspase‐dependent pathways in the oxygen–glucose deprived SHSY‐5Y cell lines: In silico and in vitro study

Rajan,

Ramanathan

2024

Chem Biol Drug Des

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JNK3, a neuronal kinase activated by stress, plays a role in stress‐induced apoptosis, leading to neuronal cell death following cerebral ischemia. This study investigates the neuroprotective effects of piceatannol (PCT) in SHSY‐5Y neuroblastoma cells after hypoxic injury and its interaction with JNK3. We analyzed the crystal coordinates, interaction energies, and amino acid interactions to determine PCT's selectivity for JNK3. The electrostatic potential was computed using density functional theory, while molecular dynamics assessed the stability and structural consistency of the JNK3‐PCT complex. We used SP600125 (SP6), a JNK3 inhibitor, as a reference compound. Additionally, we performed cell‐free JNK 1, 2, and 3 kinase assays to evaluate the isoform selectivity of PCT. Cytotoxicity and cell viability were determined by an MTT test. To assess apoptosis, we used acridine orange/ethidium bromide dual fluorescent labeling and ANNEXIN A5‐FITC flow cytometry. Western blot was used to evaluate the attenuation of JNK3 and apoptotic proteins. In silico studies revealed a stronger binding affinity between PCT and JNK3 compared to JNK1 and JNK2, which was further supported by the in vitro kinase assay. PCT‐treated cells exhibited a decrease in Cyt‐c and caspase‐3 expression and an increase in Bcl‐2 level, compared to hypoxic control (p < .001). PCT also demonstrated superior efficacy over SP6 in inhibiting JNK3 phosphorylation (p < .001). Furthermore, PCT significantly increased the expression of neuronal genes, including NgN1, neuroD2, and survivin (p < .001). In conclusion, PCT is a potential JNK3 inhibitor, since it inhibited phosphorylation and the Bcl‐2/Cyt‐C/caspase‐3‐dependent apoptotic pathway after ischemic/hypoxic insult.

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“…The MTT test and Western blot analysis showed that L-A03 inhibited the activation of JNKs in MDA-MB-231 and McF-7 cells . Through the calculation and prediction of bound free energy, ADME/tox and the optimal pharmacophore model, it was inferred that the lead molecule (Compound 48 ) had a good inhibitory effect on JNK3, with an IC 50 value of 58.17 nM, which was better than SP600125 . Bowers et al designed and synthesized a series of brain permeability and trisubstituted thiophene JNK inhibitors, and the representative Compound 49 effectively inhibited JNK1/2/3 with IC 50 values of 2, 5, and 9 nM, respectively, with an appropriate half-life and low clearance rate in mice; the brain/plasma ratio was 0.7 .…”

Section: Jnk Inhibitorsmentioning

confidence: 99%

“…88 Through the calculation and prediction of bound free energy, ADME/tox and the optimal pharmacophore model, it was inferred that the lead molecule (Compound 48) had a good inhibitory effect on JNK3, with an IC 50 value of 58.17 nM, which was better than SP600125. 89 Bowers et al designed and synthesized a series of brain permeability and trisubstituted thiophene JNK inhibitors, and the representative Compound 49 effectively inhibited JNK1/2/3 with IC 50 values of 2, 5, and 9 nM, respectively, with an appropriate half-life and low clearance rate in mice; the brain/plasma ratio was 0.7. 90 Hom et al found a series of JNK1/3 selective thiophene inhibitors through high-throughput screening, which were improved by replacement of the ester with heterocyclic rings.…”

Section: Jnk Inhibitorsmentioning

confidence: 99%

Unraveling the Design and Discovery of c-Jun N-Terminal Kinase Inhibitors and Their Therapeutic Potential in Human Diseases

et al. 2022

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c-Jun N-terminal kinases (JNKs), members of the mitogen-activated protein kinase (MAPK) family, are encoded by three genes: jnk1, jnk2, and jnk3. JNKs are involved in the pathogenesis and development of many diseases, such as neurodegenerative diseases, inflammation, and cancers. Therefore, JNKs have become important therapeutic targets. Many JNK inhibitors have been discovered, and some have been introduced into clinical trials. However, the study of isoform-selective JNK inhibitors is still a challenging task. To further develop novel JNK inhibitors with clinical value, a comprehensive understanding of JNKs and their corresponding inhibitors is required. In this Perspective, we introduced the JNK signaling pathways and reviewed different chemical types of JNK inhibitors, focusing on their structure–activity relationships and biological activities. The challenges and strategies for the development of JNK inhibitors are also discussed. It is hoped that this Perspective will provide valuable references for the development of novel selective JNK inhibitors.

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Identification and neuroprotective evaluation of a potential c-Jun N-terminal kinase 3 inhibitor through structure-based virtual screening and in-vitro assay

Cited by 9 publications

References 40 publications

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Piceatannol selectively inhibited the JNK3 enzyme and augmented apoptosis through inhibition of Bcl‐2/Cyt‐c/caspase‐dependent pathways in the oxygen–glucose deprived SHSY‐5Y cell lines: In silico and in vitro study

Unraveling the Design and Discovery of c-Jun N-Terminal Kinase Inhibitors and Their Therapeutic Potential in Human Diseases

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