GSK-J4 is a cell permeable prodrug rapidly hydrolyzed by macrophage esterases to GSK-J1, a potent selective jumonji H3K27 demethylase inhibitor. GSK-J4 inhibited TNF-α production with an IC50 of 9 μM in LPS-stimulated human macrophages and blocked the production of TNF-α by macrophages derived from patients with rheumatoid arthritis. GSK-J1 is selective for the KDM6 subfamily members JMJD3 and UTX with an IC50 of 60 nM in a JMJD3 assay, and is inactive against other demethylases of the JMJ family and over 100 tested kinases and histone deacetylases.
Mol Cancer Ther. 2021 Oct;20(10):1868-1879.
Pharmaceutical Interference of the EWS-FLI1–driven Transcriptome By Cotargeting H3K27ac and RNA Polymerase Activity in Ewing Sarcoma
GSK-J4 purchased from AbMole
Sci Transl Med. 2018 May 16.
Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma
GSK-J4 purchased from AbMole
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Source | Oncotarget (2018). Figure 4. GSK-J4 |
| Method | XTT assay | |
| Cell Lines | LNCaP and DU 145 cells | |
| Concentrations | 10 μM | |
| Incubation Time | 24 h, 48 h and 72 h | |
| Results | JMJD3 expression with GSK-J4 treatment was reduced by 61% for LNCaP and by around 20% for DU 145 and PC-3 |
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Source | Sci Transl Med (2018). Figure 4. GSK-J4 (Abmole Bioscience) |
| Method | Seventy-two–hour Cell Titer-Glo assay | |
| Cell Lines | neuroblastoma cell lines | |
| Concentrations | 1 μM | |
| Incubation Time | 72 hours | |
| Results | The venetoclax/GSK-J4 combination suppressed the growth of several MYCN-amplified neuroblastoma cell lines, which was due to an increase in the induction of apoptosis by the combination compared to GSK-J4 or venetoclax single-agent therapy |
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Source | Sci Transl Med (2018). Figure 3. GSK-J4 (Abmole Bioscience) |
| Method | Cell viability assays | |
| Cell Lines | SH-SY5Y cells | |
| Concentrations | 1 μM | |
| Incubation Time | 6 days | |
| Results | Furthermore, the combination of RA and GSK-J4 induced both the differentiation marker CHD5 and several ER stress markers, including PUMA, after 6 days of treatment |
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Source | Sci Transl Med (2018). Figure 2. GSK-J4 (Abmole Bioscience) |
| Method | Western blot | |
| Cell Lines | neuroblastoma cell lines | |
| Concentrations | 1 μM | |
| Incubation Time | 72 hours | |
| Results | Consistent with a role for PUMA in GSK-J4–mediated efficacy, RNA-seq and Western blot analyses indicated induction of BBC3/PUMA, whereas knockdown of BBC3 by short hairpin–mediated RNA (shRNA) silencing protected cells from GSK-J4–induced apoptosis/necrosis |
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Source | Sci Transl Med (2018). Figure 1. GSK-J4 (Abmole Bioscience) |
| Method | cell viability assay | |
| Cell Lines | Neuroblastoma cell lines | |
| Concentrations | 1 μM | |
| Incubation Time | 72 hours | |
| Results | GSK-J4 delivered daily was sufficient to induce tumor regressions in the IMR32 model, completely block growth in the COG-N-561 PDX, and inhibit tumor growth in the FELIX PDX and CHLA20 models |
| Molecular Weight | 417.5 |
| Formula | C24H27N5O2 |
| CAS Number | 1373423-53-0 |
| Solubility (25°C) | DMSO 20 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Histone demethylase Products |
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INCB059872 is a potent, orally active, selective and irreversible inhibitor of lysine-specific demethylase 1 (LSD1) in myeloid leukemia. |
| KDM2A/7A-IN-1
KDM2A/7A-IN-1 is a first-in-class, selective, cell-permeable inhibitor of the histone lysine demethylase KDM2A/7A, with an IC50 value of 0.16 μM for KDM2A, 75-fold more selective than other JmjC lysine demethylases, and with no effect on methyltransferases or histone acetyltransferases. KDM2A was 75 times more selective than other JmjC lysine demethylases and had no effect on methyltransferases and histone acetyltransferases. |
| NCD38 TFA
NCD38 TFA is a LSD1-selective inhibitor. |
| LSD1-IN-26
LSD1-IN-26 is a potent LSD1 inhibitor, with an IC50 of 25.3 nM. |
| JMJD6-IN-1
JMJD6-IN-1 is a JMJD6 inhibitor, with an inhibition rate of 82% at 10 μM. |
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