trans-ISRIB, ≥98%

Chemical Information:

Background: 

Integrated stress response inhibitor. Potently reverses the effects of initiation factor 2α (eIF2α) phosphorylation, IC50=5 nM1. Enhances spatial and fear-associated learning in mice and enhances cognitive function. Mechanism of action involves activation of eiF2β. Suppresses ER stress-induced inflammatory gene expression. Potently attenuates amyloid β-induced neuronal cell death (12.5-25 nM) with no effect on amyloid β production. Reverses hippocampal-dependent cognitive deficits induced by traumatic brain injury in two different injury mouse models.

The integrated stress response (ISR) is a stress response system in that down-regulates protein synthesis and upregulates expression of certain genes, in response to internal or extracellular stresses (for example, hypoxia, low glucose, viral infection, oxidant stress). The result is either the expression of genes to synthesize proteins that fix the damage in the stressed cell, or a cascade of events leading to cellular apoptosis.[1]

EIF-2 protein kinases play an important role in the ISR, as they respond to stress signals by phosphorylating the alpha-subunit of translation initiation factor 2 (eIF2), which modulates gene expression further. In normal cells, eIF2 is an important factor for translation. Phosphorylation of eIF2 converts eIF2 from a substrate to a competitive inhibitor of its nucleotide exchange factor, eIF2B, disrupting protein translation. The phosphorylated eIF2 (P-eIF2) also controls the formation of stress granules (SGs) which play a role in regulating translation of stress effector proteins.

These mechanisms are important for a healthy immune response to protect cells against damage. However, an overactive or malfunctioning ISR has negative consequences and has been linked to neurodegeneration, cognitive disorders, diabetes, and metabolic disorders.[2] Furthermore, the ISR is activated during ageing and contributes to a number of age-related cognitive issues.

ISR inhibitors were hypothesized as being usable to treat ISR-mediated neurodegeneration, but potential candidate compounds were linked to adverse effects due to limiting the effectiveness of the ISR, thus limiting immune response, and rendering the cell incapable of repairing damage.[3] [4]

Modes of action:

ISRIB is a very recent and experimental compound, and the full modes of action are not yet properly understood.

Research suggests that the new small compound, ISRIB, inhibits the integrated stress response (ISR) only under specific conditions (provided that cellular concentrations of phosphorylated transcription factor eIF2 (P-eIF2) are below a certain threshold).[5] Remarkably, ISRIB appears to modulate the ISR only when low-level ISR activity is present, but does not affect strong ISR signalling – promising results for the treatment of chronic ISR activity. It does so by acting as a ‘molecular staple’, pinning together the tetrameric subcomplexes of eIF2B.[6]

Furthermore, a neuronal model of amyotrophic lateral sclerosis (ALS) – a disease linked to folding stress in the endoplasmic reticulum (ER) – indicated that ISRIB selectively inhibited downstream PERK signalling and significantly enhanced the survival of G93A and SOD1-expressing neurons.[7]

In correlation to these results, further studies have pointed towards ISRIB’s capacity to selectively inhibit the phosphorylation of eIF2 transcription factor, thereby disrupting the ISR and formation of stress granules (SGs) and allowing translation to continue. ISRIB appears to substantially reverse the disruption of translation caused by eIF2 phosphorylation, which may be beneficial for addressing cognitive decline, neurodegeneration, and memory-loss.[8]

Further scientific research

Please note that this is not a comprehensive account of the scientific research on ISRIB to date. We have made a humble attempt to convey some of the most relevant research on the subject to date, in a variety of applications.

Meta-analyses and reviews:

So far, no meta-analyses or clinical reviews have been conducted relating to this specific compound.

Human studies and clinical trials:

To date, no human studies or clinical trials have been performed for ISRIB.

Toxicity reviews:

Due to the recent and experimental nature of this compound, toxicity studies are not yet available.

Animal studies:

A 2020 study published in eLife Journal examined the effects of ISRIB on age-related memory decline in mice. The study made several important findings that warrant further investigation.[9]

1. ISRIB was found to reset the ISR in the brain of old mice, through inhibitory effects on the ATF4 protein. Even 18 days after cessation of treatment, the ATF4 protein levels in older mice were indistinguishable from those of younger mice.
   
   
2. ISRIB-induced inhibition of the ISR reversed age-induced decline in spatial learning and memory. Old mice were treated with ISRIB and subjected to the radial arm water maze test along with younger mice (control). Remarkably, even one week after treatment, the memory performance of ISRIB-treated older mice was comparable to that of the young mice.
   
   
3. ISRIB reversed age-related changes in mouse hippocampal function, restoring neuronal function to levels similar to those of younger mice (through effects on intrinsic excitability, i.e. reducing AHP following high-frequency firing).
   
   
4. Dendritic spine loss was reduced following the treatment with ISRIB, indicating improvements in both the structure and function of neurons in old mice.
   
   
5. Treatment of old mice with ISRIB resulted in reduced expression of inflammation IFN pathway genes: Rtp4, Ifit1, and Gbp10 – to the point that these inflammation markers were indistinguishable from those of young mice.
   
   
6. In correlation with previous studies,[10] ISRIB treatment produced a reduction of P-eIF2 levels, which counteracts age-related activation of the ISR.

Precautions and Disclaimer:

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References:

[1] Curdy Nicolas, Lanvin Olivia, Cadot Sarah, Laurent Camille, Fournié Jean-Jacques, Franchini Don-Marc. (2021). Stress Granules in the Post-transcriptional Regulation of Immune Cells, Frontiers in Cell and Developmental Biology. Vol. 8, pp. 1686. DOI: https://doi.org/10.3389/fcell.2020.611185

[2] Costa-Mattioli, M., & Walter, P. (2020). The integrated stress response: From mechanism to disease. Science (New York, N.Y.), 368(6489), eaat5314. https://doi.org/10.1126/science.aat5314

[3] Moreno, J. A., Halliday, M., Molloy, C., Radford, H., Verity, N., Axten, J. M., Ortori, C. A., Willis, A. E., Fischer, P. M., Barrett, D. A., & Mallucci, G. R. (2013). Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Science translational medicine, 5(206), 206ra138. https://doi.org/10.1126/scitranslmed.3006767

[4] Dimasi, P., Quintiero, A., Shelkovnikova, T. et al. Modulation of p-eIF2α cellular levels and stress granule assembly/disassembly by trehalose. Sci Rep 7, 44088 (2017). https://doi.org/10.1038/srep44088

[5] Rabouw, H. H., Langereis, M. A., Anand, A. A., Visser, L. J., de Groot, R. J., Walter, P., & van Kuppeveld, F. (2019). Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proceedings of the National Academy of Sciences of the United States of America, 116(6), 2097–2102. https://doi.org/10.1073/pnas.1815767116

[6] Anand, A. A., & Walter, P. (2020). Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response. The FEBS journal, 287(2), 239–245. https://doi.org/10.1111/febs.15073

[7] Bugallo, R., Marlin, E., Baltanás, A. et al. Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death Dis 11, 397 (2020). https://doi.org/10.1038/s41419-020-2601-2

[8] Sidrauski, C., McGeachy, A. M., Ingolia, N. T., & Walter, P. (2015). The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. eLife, 4, e05033. https://doi.org/10.7554/eLife.05033

[9] Krukowski, K., Nolan, A., Frias, E. S., Boone, M., Ureta, G., Grue, K., Paladini, M. S., Elizarraras, E., Delgado, L., Bernales, S., Walter, P., & Rosi, S. (2020). Small molecule cognitive enhancer reverses age-related memory decline in mice. eLife, 9, e62048. https://doi.org/10.7554/eLife.62048

[10] Zyryanova, A. F., Weis, F., Faille, A., Alard, A. A., Crespillo-Casado, A., Sekine, Y., Harding, H. P., Allen, F., Parts, L., Fromont, C., Fischer, P. M., Warren, A. J., & Ron, D. (2018). Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science (New York, N.Y.), 359(6383), 1533–1536. https://doi.org/10.1126/science.aar5129