GSK126

Catalog No.S7061

GSK126 Chemical Structure

Molecular Weight(MW): 526.67

GSK126 is a potent, highly selective EZH2 methyltransferase inhibitor with IC50 of 9.9 nM, >1000-fold selective for EZH2 over 20 other human methyltransferases.

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Cited by 15 Publications

5 Customer Reviews

  • HeLa cells were transfected with NS (nonspecific) or EZH2-specific siRNA for 48 h with protease inhibitors (10 μM E64 and 10 μM pepstatin-A). Cells were stained with LC3B antibody (green) and DAPI, and observed under confocal microscopy for LC3B puncta. Scale bars: 10 μm

    Autophagy, 2015, 11(12):2309-22.. GSK126 purchased from Selleck.

    Concentration-dependent cytotoxic effect of candidate therapeutics. a. KMBC (blue circles) and HuCCT1 (purple squares) cells and b: haploid BAP1 knockout (HAP1 BAP1 KO) (green circles) or parental haploid HAP1 cells (WT) (orange squares) were plated in 384-well plates (1,000 cells/well), and incubated with varying concentrations of the indicated drug. Cell viability was assessed after 72 h using Cell Titer GloR 2.0 assay. Data represents the average percent cell viability plotted against concentration of drug in nM from 4 replicates for each condition. The table indicates the inhibitory concentration at 50% effect (IC50) values for each drug for each of the cell lines

    Mol Cancer, 2017, 16(1):22. GSK126 purchased from Selleck.

  • (C) Four GCBDLBCL cells lines [1 wild-type (wt), 3 mutated (mut) EZH2] were treated with 500 nmol/l BAY 1238097 or with an EZH2 inhibitor (DZNep and GSK126, both used at the concentration of 500 nmol/l) as single agents and in combination for 72 h. The arrow indicates the EZH2 correct band. Dimethyl sulphoxide (DMSO) alone was added as negative control cells. Membranes were hybridized with antibodies against EZH2, H3K27me3, histone H3 and GAPDH.

    Br J Haematol, 2017, 178(6):936-948. GSK126 purchased from Selleck.

    immunostaining (D) show reduced levels of H3K27me3 with increasing levels of GSK126.

    Mol Cancer Res, 2018, 16(3):417-427. GSK126 purchased from Selleck.

  • Immunohistological analysis of H3K27me3 marks in Men1WT MEFs following 72 h stimulation using 10 μM of GSK343 or 3 μM of GSK126. Representative pictures of a H3K27me3 immunofluorescent staining counterstained with DAPI are shown. Graph shows the % of cells that retain a H3K27me3 staining following treatments.

    Biochim Biophys Acta, 2017, 1860(4):427-437. GSK126 purchased from Selleck.

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Choose Selective Histone Methyltransferase Inhibitors

Biological Activity

Description GSK126 is a potent, highly selective EZH2 methyltransferase inhibitor with IC50 of 9.9 nM, >1000-fold selective for EZH2 over 20 other human methyltransferases.
Targets
EZH2 [1]
(Cell-free assay)
9.9 nM
In vitro

In vitro, GSK126 most potently inhibits H3K27me3, followed by H3K27me2 in both EZH2 wild-type and mutant DLBCL cell lines. GSK126 also effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines, and induces transcriptional activation of EZH2 target genes in sensitive cell lines. [1] In A687V EZH2-mutant cells, GSK126 treatment results in a global decrease in H3K27me3, robust gene activation, caspase activation, and decreased proliferation. [2] In parental H2087 cells, GSK126 inhibits the expression of VEGF-A and phosphorylated Ser(473)-AKT, and thus causes the inhibition of cell proliferation, migration and metastasis. [3]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human Pfeiffer cells NYWyOllJS3m2b4TvfIlkyqCjc4PhfS=> MWe3NkBp MYPDfZRwfG:6aXPpeJkh[WejaX7zeEBpfW2jbjDQ[oVq\m[ncjDj[YxteyCneIDy[ZN{cW6pIFXaTFIhSTZ4N1egcZV1[W62IHHzd4V{e2WmIHHzJIdzd3e2aDDpcohq[mm2aX;uJIFnfGW{IEeyJIhzeyCkeTDXV3QuOSCjc4PhfUwhT0l3ME2wMlE5KM7:TT6= MmXwNlQ4Pjd6NUC=
human HeLa cells MVPGeY5kfGmxbjDhd5NigQ>? MWO3NkBp MmLuTY5pcWKrdHnvckBw\iCHWliyJIlvKGi3bXHuJGhmVGFiY3XscJMh[XO|ZYPz[YQh[XNicnXkeYN1cW:wIHnuJGg{UzJ5bXWzJIxmfmWuczDpcoN2[mG2ZXSg[o9zKDd{IHjyd{BjgSCHTFnTRUBu\XSqb3SsJGlEPTB;MD6yPEDPxE1w MlLZNlYyQDlyN{i=
human U2932 cells NETVPI9EgXSxdH;4bYPDqGG|c3H5 NV;vfHZbPzJiaB?= Mo\BR5l1d3SxeHnjbZR6KGGpYXnud5QhcHWvYX6gWVI6OzJiY3XscJMh[XO|ZYPz[YQh[XNiZ4Lve5RpKGmwaHnibZRqd25iYX\0[ZIhPzJiaILzJIJ6KFeVVD2xJIF{e2G7LDDHTVUxRTZwNzFOwG0v NH;aSGYzPDd4N{i1NC=>
human PC3 cells NUm4eWZVS3m2b4TvfIlkyqCjc4PhfS=> NG\QWHg4OiCq NEjDcoVEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBRSzNiY3XscJMh[XO|ZYPz[YQh[XNiZ4Lve5RpKGmwaHnibZRqd25iYX\0[ZIhPzJiaILzJIJ6KFeVVD2xJIF{e2G7LDDHTVUxRTlwNDFOwG0v NEXJbnMzPDd4N{i1NC=>
human Daudi cells NHvSdFVEgXSxdH;4bYPDqGG|c3H5 NU\LT2dQPzJiaB?= MVnDfZRwfG:6aXPpeJkh[WejaX7zeEBpfW2jbjDEZZVlcSClZXzsd{Bie3Onc4Pl[EBieyCpcn;3eIghcW6qaXLpeIlwdiCjZoTldkA4OiCqcoOgZpkhX1OWLUGgZZN{[XluIFfJOVA:OTFwMjFOwG0v MUCyOFc3Pzh3MB?=
human T98G cells Mo\kR5l1d3SxeHnjxsBie3OjeR?= NYGyNoFYPzJiaB?= NF3F[mhEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckBVQTiJIHPlcIx{KGG|c3Xzd4VlKGG|IHfyc5d1cCCrbnjpZol1cW:wIHHmeIVzKDd{IHjyd{BjgSCZU2StNUBie3OjeTygS2k2OD1zMj62JO69VS5? NHvieIkzPDd4N{i1NC=>
human A549 cells Mn;aR5l1d3SxeHnjxsBie3OjeR?= NEXyUWY4OiCq NWWwNnhRS3m2b4TvfIlkcXS7IHHnZYlve3RiaIXtZY4hSTV2OTDj[YxteyCjc4Pld5Nm\CCjczDndo94fGhiaX7obYJqfGmxbjDh[pRmeiB5MjDodpMh[nliV2PUMVEh[XO|YYmsJGdKPTB;MUiuO{DPxE1w M{n1RlI1PzZ5OEWw
human U87MG cells MWnDfZRwfG:6aXRCpIF{e2G7 MnSwO|IhcA>? MlnYR5l1d3SxeHnjbZR6KGGpYXnud5QhcHWvYX6gWVg4VUdiY3XscJMh[XO|ZYPz[YQh[XNiZ4Lve5RpKGmwaHnibZRqd25iYX\0[ZIhPzJiaILzJIJ6KFeVVD2xJIF{e2G7LDDHTVUxRTJ6LkWg{txONg>? M{jW[|I1PzZ5OEWw

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
H3K27Me3 / EZH2; 

PubMed: 28418882     


Increasing concentrations of GSK126 consistently decreased H3K27 me3 protein levels. After HEC50B and HEC1B cells were treated with various concentrations of GSK126 (0.1–10 μM) or 0.2% DMSO for 24 h, western blotting was performed for EZH2 and H3K27 me3.

XIAP / Survivin / MCL-1 / BID / BIM / BAX / BCL-xl/ Bcl-2; 

PubMed: 27926488     


Dose- and time-dependent effects of GSK126 on apoptosis-related proteins in RPMI8226, MM.1S and LP1 cells were detected by immunoblotting. Arrows indicates the specific bands of corresponding proteins.

β-catenin / c-Myc / LEF1 / DVL2 / DVL3 / p-GSK3β; 

PubMed: 27926488     


RPMI8226, MM.1S and LP1 cells exposed with indicated concentrations of GSK126. Regulatory proteins in Wnt/β-catenin pathway were analyzed by immunoblotting.

28418882 27926488
Immunofluorescence
H3K27me3; 

PubMed: 25053977     


Representative images produced by immunostaining followed by fluorescence in situ hybridisation on RNA for H3K27me3 (green) and Xist (red) on female extraendoderm stem (XEN) cells (GHP7/9 cell line) treated or not with 2 μM GSK126 for 5 days. Arrowheads indicate the nuclear position of the inactive X chromosome coated with Xist RNA. The percentage of visible H3K27me3 accumulation on the Xist-coated X chromosome in each condition is indicated. n > 50. Scale bar = 5 μm.

25053977
Growth inhibition assay
Cell viability; 

PubMed: 28418882     


After treatment with various concentrations of GSK126 (0.025–20 μM) for 8 days, five endometrial cancer cell lines were subjected to cell viability assay. Cell viability (%) was normalized using cells treated with 0.4% dimethyl sulfoxide (DMSO). The IC50 values of GSK126 in endometrial cancer cell lines ranged from 2.37-5.07 μM.

Cell proliferation; 

PubMed: 29685965     


Antiproliferative effects of GSK126 on a panel of cancer cell lines, treated with 1, 10 and 25 µM of the compound for 4 or 5 days (MTS Cell Proliferation Assay). Error bars represent standard deviation. (Online version in colour.)

28418882 29685965
In vivo In mice bearing KARPAS-422 and Pfeiffer xenografts, GSK126 (150 mg/kg/d, i.p.) decreases global H3K27me3, increases gene expression, and thus causes marked tumour regression. [1]

Protocol

Kinase Assay:

[1]
+ Expand

EZH2 assay:

The five-member PRC2 complex (Flag–EZH2, EED, SUZ12, AEBP2, RbAp48) containing either wild-type or mutant 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). Under these conditions, the contribution from the enzyme concentration becomes relatively small and accurate estimates of Ki can be calculated. Reactions are initiated with [3H]-SAM, incubated for 30 min, quenched with the addition of 500-fold excess unlabelled SAM, and the methylated product peptide is captured on phosphocellulose filters according to the vendor supplied protocol for MSPH Multiscreen plates. Plates are read on a TopCount after adding 20 μL of Microscint-20 cocktail. Apparent Ki values are calculated using the Cheng–Prusoff relationship for a competitive inhibitor. IC50=Ki (1+[S]/Km)+[E]/2, where E is the enzyme and S is the substrate.
Cell Research:

[1]
+ Expand
  • Cell lines: 46 lymphoma cell lines
  • Concentrations: 0~10 μM
  • Incubation Time: 6 days
  • Method:

    The optimal cell seeding is determined empirically for all cell lines by examining the growth of a wide range of seeding densities in a 384-well format to identify conditions that permitted proliferation for 6 days. Cells are then plated at the optimal seeding density 24 h before treatment (in duplicate) with a 20-point two fold dilution series of GSK126 or 0.15% DMSO. Plates are incubated for 6 days at 37°C in 5% CO2. Cells are then lysed with CellTiter-Glo (CTG) and chemiluminescent signal is detected with a TECAN Safire2 microplate reader. In addition, an untreated plate of cells is harvested at the time of compound addition (T0) to quantify the starting number of cells. CTG values obtained after the 6 day treatment are expressed as a percent of the T0 value and plotted against compound concentration. Data are fit with a four-parameter equation to generate a concentration response curve and the concentration of GSK126 required to inhibit 50% of growth (growth IC50) is determined.


    (Only for Reference)
Animal Research:

[1]
+ Expand
  • Animal Models: Female beige SCID mice bearing Pfeiffer or KARPAS-422 tumors
  • Formulation: 20% captisol
  • Dosages: 150 mg/kg/day
  • Administration: i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 3 mg/mL warmed (5.69 mM)
Water Insoluble
Ethanol Insoluble warmed
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
4% DMSO+corn oil
For best results, use promptly after mixing. 		0.5mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 526.67
Formula

C31H38N6O2
CAS No. 1346574-57-9
Storage powder
in solvent
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    Could you please suggest a vehicle for in vivo uses without oil?

  • Answer:

    S7061 could be dissolved in 4% DMSO+30% PEG 300+ddH2O (0.5mg/ml).

  • Question 2:

    Does this drug require an activation step to be functional? For example, an acidic or basic environment.

  • Answer:

    GSK126 does not require an activation step to be functional.

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Histone Methyltransferase Signaling Pathway Map
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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID