1. Product Overview
GSK126 (CAS 943962-47-8), systematically named N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N-(2,2-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-5-((ethylsulfonyl)methyl)picolinamide, is a potent, selective, and S-adenosylmethionine (SAM)–competitive inhibitor of enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). With the molecular formula C₃₅H₄₄N₆O₄S and a molecular weight of 644.83 g/mol, it appears as a white to off-white solid at room temperature. GSK126 inhibits wild-type EZH2 with an IC₅₀ of 0.5–1 nM in biochemical assays and blocks H3K27 tri-methylation in cells (EC₅₀ ≈ 100–300 nM depending on line). It shows >1,000-fold selectivity over EZH1 and other methyltransferases (G9a, SUV39H1, DOT1L, PRMT1). GSK126 is a benchmark tool for studying PRC2-dependent gene repression, polycomb target re-activation, and EZH2 gain-of-function mutation–driven lymphomas. 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-potent EZH2 inhibition: SAM-competitive EZH2 inhibitor (IC₅₀ = 0.5–1 nM WT EZH2, Kd ≈ 0.2 nM); cellular H3K27me3 reduction EC₅₀ = 100–300 nM in SU-DHL-4 (EZH2 Y641N mutant) and other DLBCL lines.
• High selectivity: >1,000-fold selectivity over EZH1, G9a, GLP, SETD7, DOT1L, SUV39H1, PRMT1/5 at 1 µM; no significant effect on H3K9me3 or H3K4me3 levels.
• Reverses PRC2-mediated silencing: Reactivates tumor suppressors (e.g., CDKN2A/p16, E-cadherin) silenced by EZH2 overexpression or Y641/N/K mutations; induces G1 arrest and apoptosis in EZH2-mutant DLBCL but not wild-type.
• High purity: Typically ≥98% by HPLC (suppliers offer 98–99.9%+), suitable for Western blot (H3K27me3 ↓, H3K27me2, EZH2), ChIP-qPCR, global methylation profiling, and in vivo xenograft studies.
• Good solubility & PK: Soluble in DMSO (≥10 mg/mL; 10 mM stock), also soluble in 10% DMSO in PBS or 5% dextrose for in vivo IP/oral gavage (formulation notes vary by model); demonstrates in vivo tumor growth inhibition in EZH2-mutant DLBCL PDX at 50–150 mg/kg po qd.
• Consistent batch quality with supporting analytical data (HPLC, LC-MS, NMR, chiral purity) available; referenced in Nat. Chem. Biol. 2012 (McCabe et al.) and numerous follow-ups on EZH2 inhibitor biology.
3. Main Applications
• Epigenetics & PRC2 research: Evaluating EZH2-dependent H3K27 methylation, PRC2 target gene silencing, and Polycomb domain function in embryonic stem cells, cancer lines, and patient-derived organoids.
• Lymphoma & oncology studies: Testing differential sensitivity of EZH2 Y641/N/D/F mutant vs WT DLBCL (SU-DHL-4, KARPAS-422 vs OCI-LY1/3); combinatorial with BCL2 inhibitors (venetoclax) or HDAC inhibitors.
• Differentiation & development: Assessing EZH2 inhibition on mesenchymal stem cell (MSC) osteo/adipo differentiation, neural crest specification, and X-chromosome inactivation models.
• SAR & drug discovery: Used as the reference first-gen selective EZH2 inhibitor alongside EPZ-6438 (tazemetostat) for comparative pharmacology, resistance mechanism studies (EED bypass, SUZ12 loss).
• General research: Positive control in HMT (histone methyltransferase) inhibitor screens; ChIP-grade validation of H3K27me3 antibody specificity when treated vs untreated.
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 (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; for in vivo use prepare fresh in 10% DMSO/5% dextrose or 10% HPβCD in saline (sonicate briefly 37–40°C if needed).
• Before opening, allow the sealed vial to warm to room temperature to prevent moisture condensation. Keep container tightly closed 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
• GSK126 is a research chemical EZH2 inhibitor with significant biological activity at low nanomolar concentrations. Treat as potentially hazardous: may cause irritation to eyes, skin, and respiratory system (GHS07; H315/H319/H335).
• 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.
