ISRIB

Discovery and target identification

• Sidrauski 2013, eLife, Walter laboratory at the University of California, San Francisco (PMID: 23741617). A screen of 106,281 compounds against an ATF4-luciferase reporter produced ISRIB, with a half-maximal inhibitory concentration of 5 nanomolar for the trans isomer and 600 nanomolar for the cis isomer. In mice, intraperitoneal ISRIB at 0.25 mg/kg after each water maze trial shortened escape latency and improved probe test performance, and a single 2.5 mg/kg dose after contextual fear conditioning increased freezing at 24 hours but not at 1 hour. In rats, ISRIB injected into the amygdala increased freezing to a tone at 24 hours but not at 3 hours.
• Sidrauski 2015, eLife (PMID: 25875391) and Sekine 2015, Science (PMID: 25858979). Two groups independently identified eIF2B as the target, the first by a short hairpin RNA screen and biochemistry showing stabilisation of activated eIF2B dimers, the second by selecting ISRIB-resistant cells and finding missense mutations in the eIF2B delta subunit that reversed the effect when reintroduced by gene editing.
• Tsai 2018, Science (PMID: 29599213) and Zyryanova 2018, Science (PMID: 29599245). Cryo-electron microscopy placed ISRIB in a cleft of the human eIF2B decamer, bridging a central symmetry interface and promoting assembly of the fully active enzyme, with the second structure resolving the molecule between the beta and delta regulatory subunits.
• Sidrauski 2015, eLife (PMID: 25719440). Ribosome profiling showed that ISRIB reverses most of the translational changes caused by eIF2 phosphorylation, causes no major change in unstressed cells, blocks stress granule formation and disassembles pre-formed stress granules.

Animal studies of memory and injury

• Traumatic brain injury, mice (PMID: 28696288). ISRIB reversed hippocampal-dependent cognitive deficits in two injury models, focal contusion and diffuse concussive injury, when given weeks after the injury, and the improvement persisted after treatment stopped. Injury-suppressed long-term potentiation was fully restored.
• Repetitive mild head trauma, mice (PMID: 31884883). Repeated injury increased risk-taking behaviour in male but not female mice. A brief course of ISRIB weeks after injury reversed that behaviour and restored synaptic function in a specific population of layer 5 prefrontal neurons.
• Concussive injury and dendritic spines, mice (PMID: 36227915). Two-photon imaging in the parietal cortex showed altered spine dynamics for up to a month after injury, which brief ISRIB treatment reversed alongside the working memory deficit.
• Old mice (PMID: 33258451). In mice about 19 months old, three daily intraperitoneal injections of 2.5 mg/kg improved radial arm water maze performance measured a week later, in males (23 vehicle and 21 ISRIB, against 10 young mice) and in females (12 vehicle and 11 ISRIB), and improved a delayed matching to place task weeks later. ATF4 protein in brain was still lower 18 days after the last dose. Hippocampal CA1 spine density rose and a T cell marker in hippocampus fell to levels seen in young mice.
• Down syndrome model, mice (PMID: 31727829). The integrated stress response was active in the brains of Ts65Dn mice and in brain tissue from people with Down syndrome. Suppressing it genetically or with ISRIB reversed the translational changes and the deficits in synaptic plasticity and long-term memory in the mice.
• Prion disease, mice (PMID: 25741597). Daily ISRIB at 0.25 mg/kg from 7 weeks after inoculation raised hippocampal protein synthesis to about 70 percent of uninfected levels against 40 percent on vehicle, and none of 12 treated mice developed confirmatory clinical signs by 12 weeks against 9 of 9 on vehicle. Survival rose from 84 plus or minus 3 days to 96 plus or minus 4 days, at which point the treated mice were killed for 20 percent weight loss despite being in good health, with no clinical or neuropathological signs of prion disease.

Negative and limiting animal results

• hAPP-J20 Alzheimer's model, mice (PMID: 27781164). ISRIB at 0.25 and 2.5 mg/kg after each water maze training session did not improve learning or memory in J20 mice or in non-transgenic littermates, in groups of about 12 to 15 per arm, despite plasma levels well above the compound's half-maximal concentration. A pilot cohort showed a non-significant trend toward better long-term memory at 0.25 mg/kg that the authors could not repeat. The authors also could not detect ATF4 in brain from either genotype, so they had no marker of target engagement.
• PS19 tau and APP amyloid models, mice (PMID: 28721361). Prolonged daily ISRIB did not improve learning and memory in APP transgenic mice and did not reduce tau-related neuropathology in PS19 mice, and the authors found no evidence of stress-response dysfunction in either model to begin with. Daily dosing in the APP line was stopped for mortality (see side effects).
• Window of activation, cells (PMID: 30674674). ISRIB rescued translation when phosphorylated eIF2 was low but not once it passed a threshold, which means its effect depends on how strongly the pathway is switched on. A correction to the paper's supporting information was published in 2021 (PMID: 33875607).

Other disease models

ISRIB rescued the stability and activity of eIF2B complexes carrying Vanishing White Matter Disease mutations in cells (PMID: 29489452); improved survival of cultured neurons expressing a familial ALS mutation, where a PERK kinase inhibitor did not (PMID: 32457286); reduced amyloid-beta-induced death of cultured neurons without changing amyloid-beta production (PMID: 27569458); protected hearing and hair cells in a mouse model of cisplatin ototoxicity without reducing cisplatin's effect on head and neck cancer cells (PMID: 39333235); and was cytotoxic to aggressive prostate cancer in patient-derived models (PMID: 29720449).

Separate compounds that reached people

ISRIB itself has not been in a trial. Two later eIF2B activators have, and their results belong to them and not to ISRIB.

• DNL343 (Denali Therapeutics) is a brain-penetrant eIF2B activator designed for neurodegenerative disease (PMID: 38511649, PMID: 39287504). It was tested in phase 1 and phase 1b studies in healthy volunteers and people with ALS, where it was generally well tolerated and reduced stress response biomarkers in blood cells and cerebrospinal fluid (PMID: 40825784, ClinicalTrials.gov NCT04268784 and NCT05006352). In regimen G of the HEALEY ALS Platform Trial, 249 participants were randomised 3 to 1 to 200 mg a day of DNL343 or placebo, with 139 shared placebo participants in the analysis. The primary bayesian analysis gave a disease rate ratio of 1.04 with a 95 percent credible interval of 0.83 to 1.32 and a 0.37 probability that the ratio was below 1, so the trial showed no slowing of disease progression (PMID: 42771346, ClinicalTrials.gov NCT05842941).
• Fosigotifator, also called ABBV-CLS-7262 (Calico Life Sciences and AbbVie), is a prodrug of an eIF2B activator developed from ISRIB analogues after an earlier analogue showed cardiovascular effects in larger animals (PMID: 42153306). In regimen F of the same platform trial, 310 participants received one of two doses or placebo for 24 weeks. The posted results give a disease rate ratio of 1.06 for the group the record labels Dose 1, with a 95 percent credible interval of 0.850 to 1.324 and a posterior probability of 0.3117 that the ratio was below 1. Of the secondary measures, the ALSFRS-R total score, respiratory function, upper limb strength and activities of daily living did not separate Dose 1 from placebo, while serum neurofilament light rose more on Dose 1 than on placebo (ratio 1.092, 95 percent interval 1.011 to 1.179, p = 0.0253) (ClinicalTrials.gov NCT05740813, results posted 14 November 2025). Fosigotifator is in a phase 1b/2 open-label study in Vanishing White Matter Disease (ClinicalTrials.gov NCT05757141) and has been used in single-patient studies in Cree leukoencephalopathy (ClinicalTrials.gov NCT07272525).

What animal studies recorded

The original paper reported no overt toxicity in mice at the doses used (PMID: 23741617). In prion-infected mice, daily ISRIB at 0.25 mg/kg for about five weeks left the pancreas intact, with normal pancreatic weight and preserved exocrine and endocrine structure and no change in blood glucose, while the PERK kinase inhibitor GSK2606414 roughly halved pancreatic weight and raised blood glucose in the same model. The ISRIB-treated animals still had to be killed at about 96 days for losing 20 percent of body weight, which the authors could not explain by pancreatic damage or diabetes and attributed either to off-target effects or to the consequences of prolonged prion infection in animals that survived longer (PMID: 25741597).

A mortality signal in one transgenic line

A study at Stanford gave 5 mg/kg of ISRIB once daily to several mouse lines. C57BL/6J mice tolerated 62 consecutive days of that dose, and PS19 tau mice received it for nine weeks. In the APP amyloid line, daily dosing was stopped on day 8 because of a significant increase in mortality in the treated animals; seven APP mice died during the second week of treatment, four non-transgenic and three transgenic, all of them in ISRIB groups. The protocol was then changed to dosing only on behavioural test days at 0.25 or 2.5 mg/kg (PMID: 28721361). This is the clearest adverse finding in the published ISRIB literature.

Mechanism-based reasons for caution

The integrated stress response is protective as well as harmful. ISRIB reduced the viability of cells placed under chronic endoplasmic reticulum stress by PERK activation (PMID: 23741617). In cancer models the same action has been used deliberately: in patient-derived models of aggressive prostate cancer, ISRIB was cytotoxic to metastatic tumour cells that depend on the stress response (PMID: 29720449), and in breast cancer cells ISRIB combined with bortezomib pushed cells into a form of cell death by restoring translation (PMID: 35114585). In cultured cells carrying a mutant tRNA that causes mistranslation, the cells became resistant to ISRIB and slower to clear protein aggregates (PMID: 34718744).

Gaps

No published study reports human pharmacokinetics, a tolerated dose, long-term safety, reproductive safety or drug interactions for ISRIB. The animal work uses injections, not oral dosing, and the compound's poor solubility is the published reason it was not developed further (PMID: 42153306).