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Fig. 1 · Structure
Cat. No.
A13114
CAS No.
1346704-33-3
Formula
C31H39N7O2
Mol. Weight
541.69

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GSK343

Cat. No. A13114 CAS 1346704-33-3

EZH2 inhibitor

GSK343 is a potent histone H3-lysine 27 (H3K27) methyltransferase EZH2 inhibitor (IC= 4 nM). Diplays 1000-fold selectivity for other HMTs except EZH1 (60-fold selectivity). GSK343 inhibits H3K27 methylation in HCC1806 cells with an IC of <200nM (measured by immunofluorescence).

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Publications for GSK343

2 publications citing this product

  1. Yang PM, .et al. , Am J Cancer Res, 2019, Oct 1;9(10):2120-2139 PMID: 31720078
  2. Nie L, .et al. , Nat Commun, 2019, Nov 8;10(1):5114 PMID: 31704972
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Biological Activity

GSK343 is a potent histone H3-lysine 27 (H3K27) methyltransferase EZH2 inhibitor (IC= 4 nM). Diplays 1000-fold selectivity for other HMTs except EZH1 (60-fold selectivity). GSK343 inhibits H3K27 methylation in HCC1806 cells with an IC of <200nM (measured by immunofluorescence).

Bioactivity / Mechanism

GSK343 is a SAM-competitive inhibitor of EZH2-containing PRC2. The discovery study reported an apparent Ki of 1.2 ± 0.2 nM (SD; n = 2). In separate nucleosome assays, IC50 values were 0.004 μM for EZH2 and 0.24 μM for EZH1, indicating 60-fold selectivity over EZH1. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target Activity Value
EZH2 (Cell-free assay) 4 nM
EZH1 (Cell-free assay) 240 nM

Cellular Effect

Cell Line Activity Value Description Reference
HCC1806 IC50 174 nM Inhibition of EZH2-mediated nuclear H3K27 methylation in human HCC1806 cells after 72 hrs by immunofluorescence analysis [PMID: 24900432]
LNCaP IC50 2.9 μM Inhibition of EZH2-mediated proliferation of human LNCaP cells after 6 days by chemiluminescence analysis [PMID: 24900432]

In Vitro Studies

In HCC1806 breast cancer cells, 72-hour GSK343 treatment reduced H3K27me3 normalized to total histone H3, with a reported cellular IC50 of 174 ± 84 nM. This is an epigenetic assay endpoint, not a viability IC50. [1]

GSK343 also increased mature and nuclear SREBP2 and SREBP2 DNA-binding activity in HepG2 and PLC5 hepatocellular carcinoma cells after 6 hours at 20 μM. This additional cellular response limits interpretation of GSK343 effects solely through its intended epigenetic target. [2]

PRC2 inhibition, SAM competition and EZH1 selectivity

Biochemical assay · Recombinant five-component PRC2 containing EZH2; comparative EZH1-containing complex [1]

GSK343 inhibited EZH2-containing PRC2. Increasing SAM shifted its IC50 upward and a competitive model best fit the data. EZH1 was also inhibited, with lower potency. Apparent Ki and nucleosome-assay IC50 values derive from different assay formats.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
EZH2/PRC2 activity with histone H3 peptideApparent Ki 1.2 ± 0.2 nM[1]
EZH2-containing PRC2 activity with nucleosomesIC50 0.004 μM[1]
EZH1-containing PRC2 activity with nucleosomesIC50 0.24 μM[1]
Dependence of inhibitory potency on SAM concentrationMechanism SAM-competitive[1]

Literature-Reported Treatment Conditions

Treatment concentration
Apparent-Ki experiment: 0.6 nM–112 μM compound. Selectivity IC50 assays used a separate dilution series.
Exposure duration
30 min for the apparent-Ki peptide assay; 1 h for EZH2/EZH1 nucleosome assays.
Method
Apparent Ki: 5 nM PRC2, 10 μM histone H3(21–44) peptide, 7.5 μM radiolabeled SAM. Selectivity assays: nucleosome substrate and 0.25 μM radiolabeled SAM; see separate SI assay descriptions.
Vehicle
DMSO: 2.5% final for apparent-Ki assay. Equal-volume DMSO controls specified for selectivity assays.
Reported limits
No test-lot equivalence to the marketed product was established.
Methods and source locations

Compound reported in the paper: GSK343; Compound label in the paper: Compound 6 (GSK343)

Evidence concerns the named experimental material and model; it does not validate an Adooq lot or establish clinical efficacy.

Table 1, compound 6 and footnote a; Table 2, compound 6 and footnotes; Figure 1 and caption; SI pp. 13–15, compound 6 and Experimental Methods (Biochemistry, Biology)

EZH2/PRC2 activity with histone H3 peptide: Radiometric peptide methylation; Cheng–Prusoff calculation from IC50. Table 1 specifies standard deviation, n = 2. — Table 1, compound 6 and footnote a; SI pp. 14–15, Determination of apparent Ki values

EZH2-containing PRC2 activity with nucleosomes: Five-component complex; nucleosome/[3H]-SAM scintillation proximity assay; mean of at least two independent replicates. — Table 2, EZH2 row, compound 6, footnotes a–b; SI p. 15, In vitro biochemical assays

EZH1-containing PRC2 activity with nucleosomes: Comparative five-component EZH1 complex assay; mean of at least two independent replicates. Reported selectivity over EZH1: 60-fold. — Table 2, EZH1 row, compound 6, footnotes a–b; selectivity paragraph; SI p. 15

Dependence of inhibitory potency on SAM concentration: IC50 measured at eight SAM concentrations (3–15 μM); competitive, uncompetitive and noncompetitive models compared by F-test. — Figure 1 image/caption and mechanism paragraph; SI p. 15, Mechanism of inhibition

Cellular reduction of H3K27me3

Cell-based study · HCC1806 human breast cancer cells [1]

GSK343 reduced nuclear H3K27me3 after 72 hours. This epigenetic endpoint measures H3K27me3 normalized to total histone H3; it is not a cell-killing or proliferation IC50.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Nuclear H3K27me3 normalized to total histone H3Cellular IC50 174 ± 84 nM[1]

Literature-Reported Treatment Conditions

Treatment concentration
2 nM–38 μM, 10-point threefold dilution series
Exposure duration
72 h
Method
High-content fluorescence imaging; nuclear H3K27me3 signal normalized to total histone H3.
Vehicle
DMSO control shown in Figure 2A; final DMSO percentage for this imaging assay was not specified in the retrieved method.
Reported limits
Do not borrow the 0.147% DMSO concentration from the separate proliferation assay. Table 1 does not separately define its cellular ± term; Figure 2 caption defines SD for plotted data.
Methods and source locations

Compound reported in the paper: GSK343; Compound label in the paper: Compound 6 (GSK343)

Evidence concerns the named experimental material and model; it does not validate an Adooq lot or establish clinical efficacy.

Table 1, compound 6 and footnote b; Figure 2A–B and caption; cellular-activity paragraph; SI p. 16, H3K27me3 cell imaging assay

Nuclear H3K27me3 normalized to total histone H3: High-content immunofluorescence imaging with H3K27me3 and total-H3 antibodies; four-parameter curve fit. Table 1: at least three independent replicates. Figure 2 specifies SD error bars and at least two independent replicates for plotted data. — Table 1, compound 6, footnote b; Figure 2A–B/caption; SI p. 16

SREBP2 processing and nuclear activity in HCC cells

Cell-based study · HepG2 and PLC/PRF/5 (PLC5) human hepatocellular carcinoma cells [2]

GSK343 increased mature SREBP2, its nuclear abundance and SREBP2 DNA-binding activity. These cellular effects provide a context-dependent limitation when interpreting GSK343 as a selective epigenetic probe. The paper’s assertion that SREBP1 DNA binding was unchanged is not adopted because Figure 2C shows increased SREBP1 signal.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Mature SREBP2 in whole-cell and nuclear lysatesQualitative immunoblot response Increased mature and nuclear SREBP2[2]
Nuclear SREBP2 DNA-binding activityDirection of response Increased after 20 μM GSK343 for 6 h[2]

Literature-Reported Treatment Conditions

Treatment concentration
0–20 μM for processing; 20 μM for nuclear abundance and DNA binding
Exposure duration
6 h
Method
Whole-cell and nuclear Western blotting plus nuclear transcription-factor DNA-binding assay.
Vehicle
0 μM/untreated comparison; final solvent concentration not specified for these panels.
Reported limits
Exact replicate counts per panel are not stated; shared statistics says at least three replica. No numerical fold changes are extracted from blots or bars.
Methods and source locations

Compound reported in the paper: GSK343; Compound label in the paper: GSK343

Evidence concerns the named experimental material and model; it does not validate an Adooq lot or establish clinical efficacy.

Figure 2A–C images/caption and Results: GSK343 activates SREBP2 that promotes cancer cell survival; Materials and methods: Materials, Western blot analysis, SREBP1/2 transcriptional activity assay and Statistical analysis

Mature SREBP2 in whole-cell and nuclear lysates: Whole-cell immunoblots at 0, 5, 10 and 20 μM; nuclear immunoblots at 0 and 20 μM. Actin and Lamin B1 controls, respectively. — Figure 2A–B images/caption; Western blot and nuclear-extraction methods

Nuclear SREBP2 DNA-binding activity: SREBP1/2 transcription-factor assay using nuclear lysates; untreated comparison. Caption marks P < 0.05 for SREBP2 in each model; shared statistics: at least three replica, means and SD, Student’s t-test. — Figure 2C image/caption; SREBP1/2 transcriptional activity assay; Statistical analysis

In Vivo Studies

In a subcutaneous SK-N-BE(2) neuroblastoma xenograft model, GSK343 at 10 mg/kg by daily intraperitoneal injection for 21 days reduced tumor growth compared with PBS vehicle (n = 7 per group). Body weight did not differ significantly between groups; this alone does not establish general safety. [3]

Neuroblastoma xenograft growth under daily GSK343 treatment

Animal study · Subcutaneous SK-N-BE(2) human neuroblastoma xenografts in six-week-old female athymic nude mice [3]

Daily GSK343 reduced tumor growth compared with PBS vehicle in this 21-day xenograft experiment. Body-weight trajectories did not differ significantly. This endpoint does not establish general safety, oral suitability or exposure-response relationships.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Relative tumor growth (Figure 3B, log2-transformed)Between-group comparison p = 0.03[3]
Average body weightBetween-group difference No significant difference[3]

Conditions shared by the study groups

Route
Intraperitoneal injection
Frequency
Once daily
Treatment course
21 days
Vehicle
PBS
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
PBS vehicle control
100 μL sterile PBS		PBS vehicle, n = 7 per groupComparator tumor-growth and body-weight measurements; n = 7.[3]
GSK343
10 mg/kg/day in 100 μL PBS		PBS vehicle, n = 7 per groupLower fold change in tumor volume and relative tumor growth than vehicle; no significant difference in body weight; n = 7.[3]
PBS vehicle control
Model: Six-week-old female athymic nude mice bearing subcutaneous SK-N-BE(2) xenografts
Reported limits: No exposure measurements or comprehensive organ-toxicity evaluation for this experiment were reported in the inspected sections.
GSK343
Model: Six-week-old female athymic nude mice bearing subcutaneous SK-N-BE(2) xenografts
Reported limits: No exposure measurements or comprehensive organ-toxicity evaluation for this experiment were reported in the inspected sections.
Methods and source locations

Compound reported in the paper: GSK343; Compound label in the paper: GSK343

Evidence concerns the named experimental material and model; it does not validate an Adooq lot or establish clinical efficacy.

Figure 3A–C image/caption; Results: GSK343 decreased tumor growth in vivo; Methods: Reagents, In vivo tumor growth, Statistical analyses

Relative tumor growth (Figure 3B, log2-transformed): Tumor volume measured three times weekly after treatment began; randomized groups, n = 7 per group. Figure 3A also marks p ≤ 0.05 for indicated time-point comparisons; no exact tumor-size values are estimated. — Figure 3A–B image/caption; In vivo tumor growth methods

Average body weight: Weights assessed at baseline, weekly and at euthanasia; n = 7 per group. Shared statistical reporting uses mean ± SEM. — Figure 3C image/caption; Statistical analyses

PBS vehicle control · Figure 3A–C image/caption; Results: GSK343 decreased tumor growth in vivo; Methods: Reagents, In vivo tumor growth, Statistical analyses

GSK343 · Figure 3A–C image/caption; Results: GSK343 decreased tumor growth in vivo; Methods: Reagents, In vivo tumor growth, Statistical analyses

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 1346704-33-3
Applications EZH2 inhibitor
Formula C31H39N7O2
Molecular Weight 541.69
SMILES
CCCC1=C(C(=O)NC(=C1)C)CNC(=O)C2=C3C=NN(C3=CC(=C2)C4=CC(=NC=C4)N5CCN(CC5)C)C(C)C

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO Warmed: 1 mg/mL (1.84 mM)
Water Insoluble
Ethanol 3 mg/mL (5.54 mM)

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Verma SK, Tian X, LaFrance LV, et al. Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2 ACS medicinal chemistry letters (2012). PMID: 24900432 DOI: 10.1021/ml3003346 Source material
  2. [2] Yang PM, Hong YH, Hsu KC, et al. p38α/S1P/SREBP2 activation by the SAM-competitive EZH2 inhibitor GSK343 limits its anticancer activity but creates a druggable vulnerability in hepatocellular carcinoma American journal of cancer research (2019). PMID: 31720078 Source material
  3. [3] Bownes LV, Williams AP, Marayati R, et al. EZH2 inhibition decreases neuroblastoma proliferation and in vivo tumor growth PloS one (2021). PMID: 33690617 DOI: 10.1371/journal.pone.0246244 Source material

Publications

2 publications citing this product

  1. Yang PM, .et al. , Am J Cancer Res, 2019, Oct 1;9(10):2120-2139 PMID: 31720078
  2. Nie L, .et al. , Nat Commun, 2019, Nov 8;10(1):5114 PMID: 31704972

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