1. Epigenetics
  2. Epigenetic Reader Domain
    Histone Methyltransferase

GSK126 (Synonyms: EZH2 inhibitor; GSK2816126A)

Cat. No.: HY-13470 Purity: 99.32%
Data Sheet SDS Handling Instructions

GSK126 is a potent, highly selective inhibitor of EZH2 methyltransferase activity with IC50 of 9.9 nM.

For research use only. We do not sell to patients.
GSK126 Chemical Structure

GSK126 Chemical Structure

CAS No. : 1346574-57-9

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10 mM * 1 mL in DMSO $70 In-stock
5 mg $60 In-stock
10 mg $90 In-stock
50 mg $240 In-stock
100 mg $400 In-stock
200 mg $660 In-stock
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Customer Review

    GSK126 purchased from MCE. Usage Cited in: Oncotarget. 2015 Sep 29;6(29):27023-36.

    This includes ATF3 (Activating Transcription Factor 3) and metastasis suppressor NDRG1 (N-Myc Downstream Regulated Gene 1) that also shows an upregulation in protein expression (phosphorylated at threonine 346) with GSK126 in two EZH2 mutant cell lines by western blot.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    GSK126 is a potent, highly selective inhibitor of EZH2 methyltransferase activity with IC50 of 9.9 nM.

    IC50 & Target

    IC50: 9.9 nM (EZH2)[1]

    In Vitro

    GSK126 potently inhibits both wild-type and mutant EZH2 methyltransferase activity with similar potencies (Ki=0.5-3 nM) independent of substrate used, and is competitive with S-adenosyl-methionine (SAM) and non-competitive with peptide substrates. GSK126 is highly selective against other methyltransferases and multiple other protein classes (EZH1, IC50=680 nM)[1]. Treatment of three SCLC cell lines with GSK126, induces growth inhibition. SCLC cell lines (Lu130, H209, and DMS53) are treated with 0.5, 2, and 8 μM GSK126, and growth curve is analyzed by WST-8 assay. Inhibition of cellular growth by GSK126 treatment is observed at 8 μM in all the three cell lines, while Lu130 and H209 are more sensitive to GSK126, even at lower doses[2].

    In Vivo

    GSK126 is administered intraperitoneally at a dose volume of 0.2 mL per 20 g body weight in female beige SCID mice. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice[1].

    References
    Preparing Stock Solutions
    Concentration Volume Mass 1 mg 5 mg 10 mg
    1 mM 1.8987 mL 9.4936 mL 18.9872 mL
    5 mM 0.3797 mL 1.8987 mL 3.7974 mL
    10 mM 0.1899 mL 0.9494 mL 1.8987 mL
    Please refer to the solubility information to select the appropriate solvent.
    Kinase Assay
    [1]

    The five-member PRC2 complex (Flag-EZH2, EED, SUZ12, AEBP2, RbAp48) containing either wild-type or mutant (A677G, Y641N, Y641C, Y641H, Y641S or Y641F) EZH2 is prepared. GSK126 is dissolved in DMSO and tested at concentrations of 0.6 nM to 300 nM with a final DMSO concentration of 2.5%. In contrast to wild-type EZH2 which prefers H3K27me0 as a substrate in vitro, EZH2 Y641 mutants prefer H3K27me2 and have little activity with H3K27me0 or H3K27me1. The A677G mutant is distinct from both the wild-type and Y641 mutant forms of EZH2 in that it efficiently methylates H3K27me0, H3K27me1, and H3K27me2; therefore, histone H3 peptides (residues 21-44; 10 μM final) with either K27me0 (wild type, A677G EZH2), K27me1 (A677G EZH2), or K27me2 (A677G, Y641N, Y641C, Y641H, Y641S and Y641F EZH2) are used as methyltransferase substrates. GSK126 is added to plates followed by addition of 6 nM EZH2 complex and peptide. As the potency of GSK126 is at or near the tight binding limit of an assay run at [SAM]=Km, IC50 values are measured at a high concentration of the competitive substrate SAM relative to its Km (7.5 μM SAM where the SAM Km is 0.3 μM)[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [2]

    GSK126 is dissolved in DMSO (10 mM) and stored, and then diluted with appropriate media before use[2].

    JUB- and PTRF-introduced DMS53 cells are seeded at density of 1×103 cells/well in 96-well plate, and cellular growth is analyzed using WST-8 kit at 12, 36, 60, and 84 h. Cellular growth of Lu130, H209, and DMS53 with treatment by DZNep or GSK126 is also analyzed using WST-8 kit. DZNep is dissolved in PBS at 5 mM, and cells are cultured at the final concentration of 5 μM. GSK126 is dissolved in DMSO at 10 mM, and cells are cultured at 0.5, 2, and 8 μM[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    GSK126 is dissolved in 20% captisol adjusted to pH 4-4.5 with 1 N acetic acid[1].

    Mice[1]
    GSK126 or vehicle is administered intraperitoneally at a dose volume of 0.2 mL per 20 g body weight. Pfeiffer or KARPAS-422 cells (1×107) in 100% Matrigel are implanted subcutaneously in female beige SCID mice. Tumors are measured with calipers, and block randomized according to tumour size into treatment groups. For efficacy studies, 10 mice are randomized in each treatment group before the initiation of dosing and GSK126 treatment is initiated once the tumour volumes are approximately 200 mm3 in the Pfeiffer and KARPAS-422 studies and 500 mm3 in the KARPAS-422 intermittent dosing study. Mice are weighed and tumors measured with calipers twice weekly. Two-tailed t-tests are conducted assuming two samples of equal variance. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    526.67

    Formula

    C₃₁H₃₈N₆O₂

    CAS No.

    1346574-57-9

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    10 mM in DMSO

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    Purity: 99.32%

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    Product Name:
    GSK126
    Cat. No.:
    HY-13470
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