1. Product Overview
GSK2606414 (CAS 1263373-43-8), systematically named 3-(2,6-dichloro-4-((6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)methyl)phenoxy)propanenitrile, is a potent, selective, and ATP-competitive inhibitor of protein kinase R-like endoplasmic reticulum kinase (PERK/eIF2α kinase). With the molecular formula C₂₀H₁₇Cl₂F₃N₃O₂ and a molecular weight of 474.27 g/mol, it appears as a white to off-white solid at room temperature. GSK2606414 inhibits PERK autophosphorylation with an IC₅₀ of 0.76 nM in cell-free assays and blocks eIF2α phosphorylation in cells (IC₅₀ = 4.3 nM in HEK293), thereby modulating the unfolded protein response (UPR) and ER stress pathways. It shows >100-fold selectivity over other eIF2α kinases (GCN2, PKR, HRI) and broad kinase panel. This compound is a key pharmacological tool for studying ER stress in neurodegeneration, diabetes, cancer, and secretory cell biology. This product is supplied exclusively for laboratory research use and is not intended for clinical, diagnostic, veterinary, food, or cosmetic applications.
2. Key Features and Advantages
• Ultra-high potency and selectivity: PERK inhibitor with IC₅₀ = 0.76 nM (autophosphorylation) and 4.3 nM (cellular p-eIF2α); >100-fold selectivity over GCN2, PKR, HRI and >500-fold over 95% of the kinome.
• Clean UPR modulation: Prevents PERK-mediated eIF2α phosphorylation without affecting ATF6 or IRE1α branches of the UPR; enables dissection of PERK-specific vs global ER stress effects.
• High purity: Typically ≥98% by HPLC (suppliers also offer 99.96%), suitable for Western blot (p-eIF2α, BiP/GRP78), qPCR (CHOP/DDIT3), and cell viability assays under tunicamycin/thapsigargin challenge.
• Good solubility: Readily soluble in DMSO (≥10 mg/mL; prepare 10 mM stock in anhydrous DMSO), also soluble in DMSO:ethanol mixtures; practically insoluble in water.
• Consistent batch quality with supporting analytical data (HPLC, LC-MS, NMR) available from qualified suppliers; referenced in Nat. Chem. Biol. 2012 (Axten et al.) and numerous follow-up studies on PERK in prion disease, diabetes, and myeloma.
• Stable under recommended storage; protect from light and moisture to preserve activity over long-term -20°C storage (2–3 years).
3. Main Applications
• ER stress and UPR research: Evaluating PERK–eIF2α axis in tunicamycin- or thapsigargin-induced ER stress models; monitoring p-eIF2α, ATF4, CHOP by Western/qPCR in HEK293, MIN6, Neuro-2a, and primary neurons.
• Neurodegeneration studies: Used in prion disease, Alzheimer’s, Parkinson’s, and ALS models to test whether PERK inhibition rescues protein misfolding toxicity and restores translation of synaptic proteins.
• Diabetes and secretory cell biology: Investigating PERK role in pancreatic beta-cell ER stress, insulin biosynthesis, and islet survival under high-glucose or cytokine challenge.
• Cancer research: Testing PERK inhibition in multiple myeloma, glioblastoma, and other cancers with high basal ER stress; combinatorial studies with proteasome inhibitors or BH3 mimetics.
• General research use as a selective PERK probe in kinase inhibitor screening, eIF2α signaling dissection, and medicinal chemistry programs targeting UPR kinases.
4. Technical Specifications
5. Storage and Handling
• Store the powdered compound sealed with desiccant, protected from light; recommended storage at -20°C (long term 2–3 years). For DMSO stock solutions, aliquot and store at -80°C wrapped in foil (6 months stable) or -20°C (1 month); avoid repeated freeze–thaw cycles. Typical working stocks are 10 mM in anhydrous DMSO, stored in amber tubes.
• Before opening, allow the sealed vial to warm to room temperature to prevent moisture condensation. Keep container tightly closed and wrapped in aluminum foil when not in use.
• Handle in a well-ventilated area or fume hood. Use personal protective equipment including safety glasses, nitrile gloves, and a lab coat. Avoid inhalation of dust and contact with skin or eyes.
• Intended exclusively for laboratory research by qualified personnel; not for human or veterinary use, food, drug, or cosmetic applications.
6. Safety Overview
• GSK2606414 is a research chemical PERK inhibitor with limited toxicological data but known in vivo activity (can exacerbate pathology in some chronic ER stress models if dosed long-term). Treat as potentially hazardous: may cause irritation to eyes, skin, and respiratory system.
• In case of eye contact, rinse immediately with plenty of running water for at least 15 minutes and seek medical advice. In case of skin contact, wash thoroughly with soap and water.
• If inhaled, move the person to fresh air and keep at rest in a position comfortable for breathing. If ingested, rinse mouth and seek medical attention—do not induce vomiting unless directed by medical personnel.
• Use appropriate engineering controls (fume hood) and personal protective equipment (safety goggles, nitrile gloves, lab coat). Avoid generating dust.
• Dispose of in accordance with local regulations for chemical waste. Do not discharge into drains, waterways, or soil.
• For detailed safety information, refer to the applicable Safety Data Sheet (SDS) prior to handling.
