The jumonji histone demethylases are essential components of transcriptional chromatin complexes. GSK-J4 HCl is a cell-permeable prodrug of GSK-J1, which selectively inhibits H3K27 demethylases JMJD3 and UTX with an IC50 value of 60nM. GSK-J4 at 25μM prevented JMJD3-induced loss of nuclear H3K27me3 immunostaining in Flag-JMJD3-transfected HeLa cells. GSK-J4 treatment also increased the total nuclear H3K27me3 level in non-transfected cells. GSK-J4 at 30μM inhibited LPS-induced inflammation in human primary macrophages derived from healthy volunteers. The IC50 value of GSK-J4 for inhibiting TNF-α protein production was 9μM. GSK-J4 at a concentration of 30μM prevented LPS-induced loss of H3K27me3 associated with the TNFA TSS[2]. In dextran sodium sulphate-treated mice, treatment with 1mg/kg GSK-J4 for 5 days reduced bodyweight loss and morbidity rate compared to the control group[3].
作用机制
GSK-J4 HCl is the ethyl ester derivative of GSK-J1, a selective inhibitor of H3K27 histone demethylase JMJD3 and UTX. GSK-J1 binds in the catalytic pocket of JMJD3. The bidentate interaction between the pyridyl-pyrimidine biaryl of GSK-J1 and the catalytic metal is critical for enzyme inhibition[1].
GSK-J4 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
WT EpdSCs
10 μM
24 h
prevented H3K27me3 loss and differentiation
Nat Cell Biol. 2020 Jul;22(7):779-790.
SOX2+ EpdSCs
10 μM
24 h
prevented H3K27me3 loss and differentiation
Nat Cell Biol. 2020 Jul;22(7):779-790.
neuroblastoma cell lines
1 μM
72 h
To evaluate the sensitivity of neuroblastoma cells to GSK-J4, results showed that some cells were highly sensitive to GSK-J4, with significantly reduced cell viability.
Sci Transl Med. 2018 May 16;10(441):eaao4680.
IMR5 cells
1 μM
72 h
To analyze the gene expression changes in IMR5 cells treated with GSK-J4 through RNA sequencing, results showed that more than 7000 genes were significantly altered.
Sci Transl Med. 2018 May 16;10(441):eaao4680.
K562 cells
5 μM
24 h
Restored H3K27me3 levels
J Clin Invest. 2024 Jan 2;134(1):e163964.
K562 cells
5 μM
72 h
Inhibited cell proliferation
J Clin Invest. 2024 Jan 2;134(1):e163964.
OCI-AML5 cells
5 μM
24, 48, 72 h
Increased H3K27me3 levels and decreased GATA2 and MEIS1 expression
J Clin Invest. 2024 Jan 2;134(1):e163964.
ER-Hoxb8 cells
5 µM
3 days
GSK-J4 treatment significantly decreased S100a8 and S100a9 mRNA levels in WT ER-Hoxb8 cells, while the effects on C/EBPδ KO cells were negligible
Elife. 2022 May 11;11:e75594.
lung cancer cells
1 µM
5 days
GSK-J4 was more toxic in SMARCA4-defective lung cancer cells, with a five-fold lower EC50 than in MYCamp cells
Nat Commun. 2021 Jul 14;12(1):4319.
ovarian cancer cells
1 µM
5 days
GSK-J4 strongly suppressed cell viability and clonogenic capability in SMARCA4-defective ovarian cancer cells
Nat Commun. 2021 Jul 14;12(1):4319.
osteoprogenitors
1 μM
30 min
GSK-J4 blocked the activation of MKP-1 by dexamethasone and restored the protein levels of p-JNK, p-ERK, p-p38, and PCNA, indicating that GSK-J4 alleviates the inhibitory effect of dexamethasone on osteoprogenitor proliferation by inhibiting H3K27me3 demethylation.
Commun Biol. 2024 Nov 28;7(1):1589.
SF8628 K27M DIPG cells
6 μM
6, 24, 48, 72 h
GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility, inhibiting DNA DSB repair.
Clin Cancer Res. 2019 Sep 15;25(18):5572-5583.
DIPG-007 K27M DIPG cells
6 μM
6, 24, 48, 72 h
GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility, inhibiting DNA DSB repair.
Clin Cancer Res. 2019 Sep 15;25(18):5572-5583.
SF9427 H3 wild-type GBM cells
6 μM
72 h
GSK-J4 did not alter the expression of DNA DSB repair genes in H3 wild-type GBM cells.
Clin Cancer Res. 2019 Sep 15;25(18):5572-5583.
143B cells
15 μM
72 h
To evaluate the effect of GSK-J4 on 143B cells, the results showed that GSK-J4 treatment increased H3K27me3 levels and enhanced the sensitivity of cells to cisplatin.
Clin Epigenetics. 2019 Jan 16;11(1):8.
HOS cells
15 μM
72 h
To evaluate the effect of GSK-J4 on HOS cells, the results showed that GSK-J4 treatment increased H3K27me3 levels and enhanced the sensitivity of cells to cisplatin.
Clin Epigenetics. 2019 Jan 16;11(1):8.
GSK-J4 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Tumor model
Intraperitoneal injection
10 mg/kg
Daily for five days
Prevented tumor differentiation
Nat Cell Biol. 2020 Jul;22(7):779-790.
Mice
Nestin-GFP mice
Intraperitoneal injection
100 mg/kg
Daily for 2 weeks
To investigate the effect of GSK-J4 on the number of Nestin-GFP positive cells, results showed that GSK-J4 significantly increased the number of Nestin-GFP positive cells.
Nat Commun. 2017 Nov 3;8(1):1312
Mice
KRAS+/Trp53-null lung cancer model
Intraperitoneal injection
100 mg/kg
Once daily for 10 days
GSK-J4 inhibits the growth of Ezh2-deficient tumors.
Nat Commun. 2023 Jan 20;14(1):336
Mice
CHLA20 and IMR32 xenograft models
Intraperitoneal injection
100 mg/kg
5 days/week, throughout the experiment
To evaluate the antitumor activity of GSK-J4 in vivo, results showed that GSK-J4 significantly inhibited tumor growth and induced tumor regression.
Sci Transl Med. 2018 May 16;10(441):eaao4680.
Mice
Asxl1Y588XTg leukemic mouse model
Intraperitoneal injection
50 mg/kg
5 times per week for 5 weeks
Reduced leukemic cell engraftment and tumor burden
J Clin Invest. 2024 Jan 2;134(1):e163964.
Mice
Orthotopic lung and ovarian cancer models
Intraperitoneal injection
50 mg/kg
Once daily for 4 weeks
GSK-J4 significantly prolonged the survival of mice with SMARCA4-defective lung and ovarian tumors and reduced tumor growth
Nat Commun. 2021 Jul 14;12(1):4319.
Mice
PDE model
Intraperitoneal injection
100 mg/kg
Daily from GD12 until labor
GSK-J4 treatment significantly restored the trabecular area and Osterix+ cell area in the metaphyseal bone of PDE young mice offspring, indicating that GSK-J4 alleviates the negative impact of PDE on osteoprogenitor proliferation and bone development by inhibiting H3K27me3 demethylation.
Commun Biol. 2024 Nov 28;7(1):1589.
Athymic mice
SF8628 K27M DIPG xenograft model
Intraperitoneal injection
100 mg/kg
Once daily for 10 consecutive days
GSK-J4 monotherapy significantly inhibited tumor growth and extended survival, and the combination therapy with radiation outperformed monotherapy.
Clin Cancer Res. 2019 Sep 15;25(18):5572-5583.
Nude mice
Osteosarcoma xenograft model
Intraperitoneal injection
50 mg/kg
Once daily until the end of the experiment
To evaluate the effect of GSK-J4 on the osteosarcoma xenograft model, the results showed that GSK-J4 combined with cisplatin significantly reduced the size and weight of tumors and enhanced tumor cell apoptosis.
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