What is the mechanism of action of Trans ISRIB A-17?

Trans ISRIB A-17 binds and stabilizes the eIF2B complex (a guanine nucleotide exchange factor), reversing the allosteric inhibition of eIF2B by phosphorylated eIF2alpha and thus restoring protein translation in stressed cells. Its IC50 for PERK signaling is approximately 5 nM, acting downstream of eIF2alpha phosphorylation.

What is the purity and how should Trans ISRIB A-17 be stored?

Purity is >99% (HPLC), appearance is a white solid. Store at -20C protected from light as a lyophilized solid; the solid is stable for 36 months. Solutions should be aliquoted and stored at -20C and used within 3 months to avoid freeze-thaw cycles.

Trans ISRIB A-17 (CAS 1628478-15-8) In Stock | Integrated Stress Response Inhibitor, eIF2B Activator

Trans ISRIB A-17 CAS 1628478-15-8
Potent Integrated Stress Response Inhibitor

Name: Trans ISRIB A-17
Brand: Trans ISRIB A-17
SKU: ISRIB-A17-TRANS
Price: Inquiry USD
Availability: InStock
Rating: 4.9 (127 reviews)

High-purity trans-ISRIB (trans-isomer). Stabilizes the eIF2B complex, reverses eIF2alpha-phosphorylation translational repression, and restores protein synthesis in stressed cells. PERK signaling IC50 ~5 nM, purity >99%. Small-batch production now active with 100g+ stock on hand.

ISR Inhibitor eIF2B Activator PERK Pathway Translation Control Purity >99%

Request a Quote Technical Specs

~5 nM

IC50 (PERK)

>99%

Purity (HPLC)

100g+

In-Stock

Molecular Information

Name: Trans ISRIB A-17
CAS: 1628478-15-8
Formula: C22H24Cl2N2O4
MW: 451.34 g/mol
SMILES: O=C(COc1ccc(Cl)cc1)NC1CC
C(NC(=O)COc2ccc(Cl)cc2)CC1
InChIKey: HJGMCDHQPXTGAV
-UHFFFAOYSA-N
LogP: 4.49 PSA: 76.66
Appearance: White solid

🧪

CAS Number

1628478-15-8

⚖️

Molecular Weight

451.34

🎯

IC50

~5 nM

✅

Purity

>99%

Product Technical Specifications

Complete physicochemical properties and quality control data for Trans ISRIB A-17; a COA report accompanies every batch

📋 Physicochemical Properties

Product NameTrans ISRIB A-17
Synonymstrans-ISRIB / ISRIB (trans-isomer)
CAS Number1628478-15-8
Molecular FormulaC22H24Cl2N2O4
Molecular Weight451.34 g/mol
SMILESO=C(COc1ccc(Cl)cc1)NC1CCC(NC(=O)COc2ccc(Cl)cc2)CC1
InChIKeyHJGMCDHQPXTGAV-UHFFFAOYSA-N
AppearanceWhite solid
Density1.3 ± 0.1 g/cm3
Boiling Point719.0 ± 60.0 °C (760 mmHg)
Flash Point388.6 ± 32.9 °C
LogP4.49
PSA76.66 Å²
Refractive Index1.603

🔬 Quality Control

Purity (HPLC)>99%
Isomer Formtrans (active isomer)
TargeteIF2B / ISR Pathway
IC50 (PERK signaling)~5 nM
Action TypeInhibitor
Storage-20°C, protect from light
Solid Stability36 months
Solution Stability-20°C aliquoted, 3 months
SolubilityDMSO ≥30 mg/mL
QC DocumentsCOA / HPLC / NMR / MS
Pack Sizes10mg / 25mg / 50mg / 100mg
Bulk SupplyGram to 100g+ custom
Stock StatusIn Stock
Use StatementResearch use only

Mechanism of Action: How ISRIB Inhibits the Integrated Stress Response

ISRIB (Integrated Stress Response Inhibitor) targets the eIF2B complex and restores protein translation downstream of eIF2alpha phosphorylation, reversing stress-induced translational arrest

Stress Signals Activate

Hypoxia, viral infection, ER stress and other cues activate four kinases — PERK, GCN2, PKR and HRI — which phosphorylate eIF2alpha at Ser51.

Translation Is Repressed

Phosphorylated eIF2alpha binds and inhibits the guanine nucleotide exchange factor eIF2B, blocking GDP→GTP exchange on eIF2 and globally suppressing protein synthesis.

ISRIB Binds eIF2B

ISRIB acts as a molecular "staple" inserted deep into the eIF2B beta/delta subunit interface, pinning two symmetrical subcomplexes together and stabilizing eIF2B's active conformation.

Translation Restored

Stabilized eIF2B resists the allosteric inhibition by phosphorylated eIF2alpha; GEF activity recovers, protein translation restarts, and cell function and cognition are restored.

This mechanism was discovered by Peter Walter's team at UCSF (eLife, 2013; Science, 2018) and structurally validated by the Cambridge and RIKEN teams (Molecular Cell, 2021). ISRIB is licensed to Calico (Alphabet/Google) for translational research on aging and neurodegeneration.

Research Areas & Applications

Trans ISRIB A-17 has broad utility across frontier biomedical fields and is a core tool molecule for ISR-pathway research

🧠

Memory & Cognitive Enhancement

Significantly enhances long-term memory consolidation and spatial learning in mouse models by releasing the eIF2alpha-phosphorylation brake on long-term potentiation (LTP) — a "cognitive brake-release".

eLife 2013

🩹

Traumatic Brain Injury Recovery

Completely eliminates learning and memory deficits in concussed mice, reversing the persistently activated ISR stress response after TBI and restoring neuronal protein synthesis.

UCSF Research

🧬

Neurodegenerative Disease

Attenuates beta-amyloid (Aβ)-induced neuronal death and shows protection across multiple neurodegeneration models, offering intervention leads for Alzheimer's and related disorders.

Neuroprotection

🎗️

Oncology & Chemosensitization

Enhances sensitivity of glioblastoma (GBM) cells to temozolomide (TMZ) and hypoxia-induced apoptosis — the ISR pathway is a key node in tumor stress adaptation.

Oncology

😔

Chronic Stress & Depression

Improves chronic-restraint-stress (CRS)-induced depressive-like behavior, increases sucrose preference and reduces immobility in forced-swim tests, implicating ISR in mood disorders.

Psychiatry Models

🦠

Infection & Immunity

In Mycobacterium tuberculosis infection models, blocks PKR-mediated eIF2alpha phosphorylation and pulmonary granuloma necrosis, revealing ISR's role in host-pathogen interplay.

Immunology

⚗️

Proteostasis Research

A classic tool molecule for translational homeostasis, used to dissect the ISR/UPR pathway, stress-granule assembly, and protein-synthesis regulation mechanisms.

Basic Research

💊

Drug Discovery Lead

ISRIB structure-activity-relationship work has yielded novel analogs with EC50 as low as 600 pM, supporting lead optimization and clinical translation.

Medicinal Chemistry

📈

Aging Biology

Licensed to Calico (Alphabet) for translational research into aging-related cognitive decline and neurodegeneration, exploring ISR-targeted anti-aging strategies.

Translational Medicine

Key Literature References

High-impact publications on ISRIB for experimental-design reference

Sidrauski C, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife. 2013;2:e00498.

doi: 10.7554/eLife.00498

Sidrauski C, et al. The small molecule ISRIB reverses the effects of eIF2alpha phosphorylation on translation and stress granule assembly. eLife. 2015;4:e05033.

doi: 10.7554/eLife.05033

Tsai JC, et al. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science. 2018;359(6383):eaaq0939.

doi: 10.1126/science.aaq0939

Zyryanova AF, et al. ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B. Molecular Cell. 2021;81(1):88-103.e6.

doi: 10.1016/j.molcel.2020.10.031

Zyryanova AF, et al. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science. 2018;359(6383):1533-1536.

doi: 10.1126/science.aar5129

Zhou W, et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. eLife. 2015;4:e07314.

doi: 10.7554/eLife.07314

In-Stock Sizes & Ordering

100g+ in-stock inventory; research packs and gram-to-hundred-gram custom batches supported; COA provided with every shipment

Tier	Pack Size	Stock Status	Suitable For	Lead Time
Research Small	10 mg	In Stock	Cell assays, screening	Same/next-day ship
Research Medium	25 mg / 50 mg	In Stock	Animal studies, mechanism	Same/next-day ship
Research Large	100 mg	In Stock	Long-term projects, multi-batch	Same/next-day ship
Custom Batch	Gram scale (1 g+)	Made-to-order	Process scale-up, collaborations	Quote to confirm
Bulk Supply	10 g ~ 100 g+	Negotiable	Pre-commercial, CDMO	Batch delivery

💡 Reference sizes above; for exact pricing please contact us for a quote. Bulk orders qualify for tiered discounts and custom purity/particle-size options.

Frequently Asked Questions (FAQ)

What is the CAS number of Trans ISRIB A-17, and how does it differ from the cis isomer?

The CAS number of Trans ISRIB A-17 is 1628478-15-8, corresponding to the trans-isomer — the biologically active form. The cis isomer has markedly lower activity. We supply the high-purity trans isomer (>99%, HPLC-verified isomer ratio).

What is the mechanism of action and target of Trans ISRIB A-17?

Trans ISRIB A-17 binds and stabilizes the eIF2B complex (the guanine nucleotide exchange factor), forming a "molecular staple" at the beta/delta subunit interface that reverses the allosteric inhibition of eIF2B by phosphorylated eIF2alpha, restoring protein translation in stressed cells. Its IC50 for PERK signaling is ~5 nM, acting downstream of eIF2alpha phosphorylation.

What research areas is Trans ISRIB A-17 suitable for?

Widely used in: neurodegenerative disease (Alzheimer's, Aβ-toxicity models), traumatic brain injury recovery, memory & cognitive enhancement, glioblastoma chemosensitization, chronic-stress depression models, Mycobacterium tuberculosis infection, proteostasis & stress-granule studies, and drug lead optimization. A core tool molecule for ISR/UPR pathway research.

What is the purity, and how should it be stored? Shelf life?

Purity >99% (HPLC), white solid. Store -20°C protected from light as a lyophilized solid — stable for 36 months. In solution, aliquot and store at -20°C, use within 3 months, and avoid repeated freeze-thaw. Every batch ships with COA, HPLC trace, NMR and MS reports.

Is it in stock? Is bulk purchase supported? What is the minimum order quantity?

Small-batch production is active with 100g+ stock available. We offer 10mg/25mg/50mg/100mg research sizes and support gram-to-hundred-gram custom batches. Research packs typically start at 10mg; bulk orders are negotiable with tiered discounts. In-stock items ship same/next day; custom batches per agreement.

What is the relationship between ISRIB and PERK inhibitors? Is ISRIB a PERK inhibitor?

ISRIB acts downstream of eIF2alpha phosphorylation rather than directly inhibiting PERK kinase itself; it activates eIF2B to counter the repressive effect of phosphorylated eIF2alpha. It is therefore effective against eIF2alpha phosphorylation driven by all four ISR kinases (PERK, GCN2, PKR, HRI), making it a broad "brake-release" agent for the ISR pathway; it is commonly classified as a PERK signaling inhibitor (IC50 ~5 nM) in the literature.

How do I dissolve ISRIB? Recommended stock-solution preparation?

ISRIB has poor aqueous solubility. Prepare stock solutions in DMSO (≥30 mg/mL); DMF is also acceptable. For animal studies, use 50% PEG300 + 50% saline to make a suspension (~0.83 mg/mL) with sonication (<60°C). Prepare fresh and aliquot for frozen storage to avoid freeze-thaw.

Are QC reports provided? Can samples be supplied for evaluation?

Every batch ships with a COA including HPLC purity, NMR structural confirmation, and MS data; MSDS and solubility datasheets are available on request. Sample-evaluation policy is available on request — long-term partners may request small samples for validation.

What is the discovery history and patent/licensing status of ISRIB?

ISRIB was discovered in 2013 by the team of Peter Walter (HHMI investigator at UCSF) through a screen of ~100,000 compounds (eLife, 2013). UCSF licensed ISRIB to Calico (Alphabet/Google) for translational research in aging and neurodegeneration. Multiple Science/eLife papers describe its structure-activity relationships.

Need Trans ISRIB A-17 in stock?

100g+ inventory ready · Purity >99% · COA included · Same-day shipping
Research packs and bulk custom orders both welcome — request a quote today

View Sizes & Request a Quote →

CAS 1628478‑15‑8 trans‑ISRIB A17 Powder ISR‑IN‑1 Blood‑Brain‑Barrier Permeable Small‑Molecule for Neurodegeneration Research