Structure of GSK-J4
CAS No.: 1373423-53-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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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 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
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.
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In Vitro:
Cell Line
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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 |
Tags: GSK-J4 | Histone Demethylase | JMJD3 inhibitor | UTX inhibitor | H3K27me3 demethylases | LPS-induced TNF-α | apoptosis | endoplasmic reticulum stress | H3K27me3/me2 | dendritic cell | TGF-β | Th1 | Th17 | demethylase | 1373423-53-0
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