ISRIB

Overview

ISRIB is a non-peptide small-molecule eIF2B activator (bis-chlorophenoxyacetamide-cyclohexane class) that antagonizes the integrated stress response (ISR) by stabilizing the eIF2B guanine-nucleotide exchange factor complex. It is not an approved drug and has no completed human clinical trials or validated human safety or efficacy data. Chemically distinct eIF2B-activator analogs (DNL343, ABBV-CLS-7262) have reached human trials, but DNL343 missed primary endpoints in a Phase 2/3 ALS trial (January 2025). ISRIB is sold by reagent suppliers for research use only.

Mechanism of Action

ISRIB binds at a symmetric interface within the decameric eIF2B guanine-nucleotide exchange factor complex (contacting the delta subunit, eIF2B4) and stabilizes the more active eIF2B assembly. This antagonizes the inhibitory effect of phosphorylated eIF2-alpha (eIF2a-P) on eIF2B's GEF activity, restoring eIF2-GTP recycling and general translation initiation that would otherwise be suppressed during activation of the integrated stress response. Reported potency IC50 ~5 nM in reversing eIF2a-P-mediated translational repression.

Research Summary

No completed or published human clinical trials of ISRIB itself exist; it has no validated human pharmacokinetic, safety, or efficacy data. In mice, systemic ISRIB enhanced spatial and fear-associated long-term memory in healthy animals, reversed hippocampus-dependent spatial-learning and working-memory deficits weeks after traumatic brain injury, and reset elevated ISR activity in aged (18–24 month) mice, reversing age-related spatial-memory decline with a brief 3-day dosing course. In prion-disease transgenic mice, ISRIB partially restored protein synthesis and prevented neurodegeneration without the pancreatic exocrine toxicity seen with PERK-inhibitor approaches. In vitro and in a patient-derived xenograft mouse model, ISRIB combined with imatinib attenuated RAS/RAF/MAPK and STAT5 signaling and eliminated therapy-resistant chronic myeloid leukemia cells.

Vendors selling ISRIB

Scored vendors carrying ISRIB, ranked by trust grade. Grades are computed from indexed Certificates of Analysis. Full $/mg pricing is on the comparison page.

Reported Side Effects

• No validated human safety profile; tolerability and adverse-event rates unknown
• Unresolved target specificity and long-term safety concerns (2024 review)
• Sustained global translational de-repression carries unquantified risk in chronic dosing
• Plausible off-target effects on stressed/malignant cells reliant on ISR signaling
• WADA prohibited-list status undetermined (not identified as named entry)

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Research References

• Pharmacological brake-release of mRNA translation enhances cognitive memory. 2013. PMID 23741617.
• The small molecule ISRIB reverses the effects of eIF2a phosphorylation on translation and stress granule assembly. 2015. PMID 25719440.
• Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. 2015. PMID 26173178.
• ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. 2021.

Frequently asked questions

Has ISRIB been independently lab-tested?

Disclosed Labs has collected 1 Certificate of Analysis (COA) for ISRIB from 1 independent testing lab. 1 vendor has submitted material for testing. Products average 99.8% tested purity across the corpus. Full testing data is available at https://www.disclosedlabs.com/peptides/isrib/testing.

Where can researchers source ISRIB?

1 vendor with Disclosed Labs trust grades currently list ISRIB, including Kimera Chems. Compare live prices and lab-verified COAs at https://www.disclosedlabs.com/prices/isrib.

How does ISRIB work?

ISRIB binds at a symmetric interface within the decameric eIF2B guanine-nucleotide exchange factor complex (contacting the delta subunit, eIF2B4) and stabilizes the more active eIF2B assembly. This antagonizes the inhibitory effect of phosphorylated eIF2-alpha (eIF2a-P) on eIF2B's GEF activity, restoring eIF2-GTP recycling and general translation initiation that would otherwise be suppressed during activation of the integrated stress response. Reported potency IC50 ~5 nM in reversing eIF2a-P-mediated translational repression.

What does the research say about ISRIB?

No completed or published human clinical trials of ISRIB itself exist; it has no validated human pharmacokinetic, safety, or efficacy data. In mice, systemic ISRIB enhanced spatial and fear-associated long-term memory in healthy animals, reversed hippocampus-dependent spatial-learning and working-memory deficits weeks after traumatic brain injury, and reset elevated ISR activity in aged (18–24 month) mice, reversing age-related spatial-memory decline with a brief 3-day dosing course. In prion-disease transgenic mice, ISRIB partially restored protein synthesis and prevented neurodegeneration without the pancreatic exocrine toxicity seen with PERK-inhibitor approaches. In vitro and in a patient-derived xenograft mouse model, ISRIB combined with imatinib attenuated RAS/RAF/MAPK and STAT5 signaling and eliminated therapy-resistant chronic myeloid leukemia cells.