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Chemical Structure| 1373423-53-0 Chemical Structure| 1373423-53-0

Structure of GSK-J4
CAS No.: 1373423-53-0

Chemical Structure| 1373423-53-0

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GSK J4 is a cell permeable prodrug rapidly hydrolyzed by macrophage esterases to GSK-J1, a potent selective jumonji H3K27 demethylase inhibitor and attenuates lipopolysaccharide (LPS)-induced proinflammatory cytokine production in primary human macrophages (IC50 = 9 μM for the inhibition of TNFα release).

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Product Details of GSK-J4

CAS No. :1373423-53-0
Formula : C24H27N5O2
M.W : 417.50
SMILES Code : O=C(OCC)CCNC1=NC(C2=NC=CC=C2)=NC(N3CCC4=CC=CC=C4CC3)=C1
MDL No. :MFCD22683852
InChI Key :WBKCKEHGXNWYMO-UHFFFAOYSA-N
Pubchem ID :71729975

Safety of GSK-J4

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Related Pathways of GSK-J4

epigenetics

Isoform Comparison

Biological Activity

Description
GSK-J4, acting as a robust dual inhibitor of the demethylases JMJD3/KDM6B and UTX/KDM6A with IC50 values of 8.6 μM and 6.6 μM respectively, curbs LPS-induced TNF-α output in human primary macrophages with an IC50 of 9 μM. It effectively maintains H3K27me3 levels in the nucleus, notably reducing the expression of multiple LPS-driven cytokines, including TNF-α.

In Vitro:

Cell Line
Concentration Treated Time Description References
K27M mutant brainstem glioma cell line SF7761 1.3–3.0 μM 72 hours GSKJ4 treatment of K27M-expressing cells revealed a dose-dependent inhibition of cellular viability, with 50% growth inhibition reached at concentrations of 1.3–3.0 μM PMC4257862
K27M mutant brainstem glioma cell line SF8628 1.3–3.0 μM 72 hours GSKJ4 treatment of K27M-expressing cells revealed a dose-dependent inhibition of cellular viability, with 50% growth inhibition reached at concentrations of 1.3–3.0 μM PMC4257862
K27M mutant human astrocytes 1.3–3.0 μM 72 hours GSKJ4 treatment of K27M-expressing cells revealed a dose-dependent inhibition of cellular viability, with 50% growth inhibition reached at concentrations of 1.3–3.0 μM PMC4257862
T-ALL cells 2µM 72 hours GSK-J4 significantly affected the growth of T-ALL cell lines, leading to cell cycle arrest and increased apoptosis. PMC4209203
Primary human T-ALL cells 2µM 72 hours GSK-J4 significantly affected the growth of primary human T-ALL cells, leading to cell cycle arrest and increased apoptosis. PMC4209203
neuroblastoma cell lines 1 μM 72 hours To evaluate the sensitivity of neuroblastoma cell lines to GSK-J4, results showed that some cell lines were highly sensitive to GSK-J4, with significant reduction in cell viability. PMC6200133
IMR5, LAN5, SK-N-F1, SK-N-BE(2) 1 μM 72 hours To analyze gene expression changes in neuroblastoma cell lines treated with GSK-J4 using RNA sequencing, results showed that sensitive cell lines had significant changes in over 7000 genes, while resistant cell lines had changes in fewer than 1500 genes. PMC6200133
Npc1−/− OPCs 0.5 µM 4 days GSK-J4 increased H3K27me3 expression and rescued the maturation of Npc1−/− OPCs to wild type levels. PMC10322873
SMARCA4def cells 1 µM 5 days Tested the effects of GSK-J4 on the growth of SMARCA4def cells, found that GSK-J4 was more toxic to these cells with a five-fold lower EC50 than in MYCamp cells PMC8280185
MYCamp cells 1 µM 5 days Tested the effects of GSK-J4 on the growth of MYCamp cells, found that GSK-J4 was less toxic to these cells PMC8280185
143B cells 10 μM 48 hours After GSK-J4 treatment, the punctas of HOXB8 and FOSL1 were markedly decreased in the nuclei, indicating that GSK-J4 inhibits the formation of CRC condensates. PMC8529446
143B cells 5 μM 48 hours After GSK-J4 treatment, the condensates could not recover fluorescence after photobleaching, indicating that GSK-J4 inhibits the liquid-like behavior of HOXB8 and FOSL1. PMC8529446
K562 cells 5 μM 24 hours GSK-J4 dramatically inhibited the growth of K562 cells and increased H3K27me3 levels. PMC10760961
OCI-AML5 cells 5 μM 24, 48, 72 hours GSK-J4 increased H3K27me3 levels in OCI-AML5 cells and decreased the expression of GATA2 and MEIS1. PMC10760961
Rat primary HSCs 5 μM GSK-J4 inhibits JMJD3, enhances cell growth, promotes morphological transition from quiescent HSCs to myofibroblast, reinforces H3K27me3, and upregulates fibrotic markers. PMC7681085

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
athymic mice SF8628 K27M xenograft model intraperitoneal injection 100 mg/kg once daily, 5 days/week for 3 weeks GSKJ4 significantly inhibited the growth of SF8628 subcutaneous tumors and significantly extended animal survival PMC4257862
Mice Collagen-induced arthritis (CIA) model Intraperitoneal injection 10 mg/kg Daily until the end of the experiment GSK-J4 significantly attenuated the severity of arthritis in CIA mice, reducing joint inflammation and pathological changes, indicating its anti-arthritic effect through JMJD3 inhibition. PMC6804949
mice CHLA20, IMR32, FELIX, COG-N-561 intraperitoneal injection 20 mg/kg Daily until the end of the experiment (day 40) To evaluate the antitumor activity of GSK-J4 in neuroblastoma mouse models, results showed that GSK-J4 significantly inhibited tumor growth, with tumor regression observed in some models. PMC6200133
mice SMARCA4def lung cancer orthotopic mouse models intraperitoneal 50-100 mg/kg daily or 4-5 days a week for several weeks Tested the anti-tumor effects of GSK-J4 on SMARCA4def lung cancer orthotopic mouse models, found that GSK-J4 significantly increased the overall and median survival of the mice PMC8280185
BALB/c nude mice orthotopic osteosarcoma xenograft model intraperitoneal injection 10 mg/kg Daily for the duration of the ABA experiment GSK-J4 treatment significantly inhibited the growth and metastasis of osteosarcoma and showed no toxicity to major organs. PMC8529446
mice NSG mice intraperitoneal injection 50 mg/kg body weight every other day for 5 weeks GSK-J4 significantly extended the survival of NSG mice xenografted with K562 cells and reduced the leukemia burden. PMC10760961

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.40mL

0.48mL

0.24mL

11.98mL

2.40mL

1.20mL

23.95mL

4.79mL

2.40mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

References

 

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