GSK-J4

Biological Activity

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.

Product Citations

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  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

Customer Product Validations & Biological Datas

	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

	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

	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

	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

	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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Kruidenier L, et al. Nature. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.