The overexpression of the Jumonji family of histone demethylases is associated with significantly lower survival in patients with breast cancer. JIB-04 is a small molecule inhibitor of the Jumonji enzymes. The IC50 values of JIB-04 for Jarid1A, JMJD2A, JMJD2B, JMJD2C, JMJD2E, and JMJD3 were 230 ± 40, 445 ± 30, 435 ± 70, 1100 ± 200, 340 ± 50, and 855 ± 5nM, respectively. JIB-04 exhibits high selectivity for cancer cells versus normal cells. The IC50 values of JIB-04 for lung and prostate cancer cell lines were as low as 10nM. Specifically, the IC50 values of JIB-04 for H358 and A549 lung cancer cells were 100 and 250nM, respectively. In immune-competent BALB/c mice inoculated with H358 or A549 lung cancer cells, administration of JIB-04 (H358 xenografts: 110mg/kg, intraperitoneal injection; A549 xenografts: 55mg/kg, oral gavage) two to three times weekly significantly decreased final tumor weights without affecting overall body weight or general health. The H358 and of A549 tumors isolated from the mice treated with JIB-04 also showed reduced total H3K9me3 demethylase activity compared to those collected from the vehicle-treated group. JIB-04 treatment also significantly extended the survival of tumor-bearing mice (18% increase in life span).[3]
作用机制
JIB-04 is pyridine hydrazine that inhibits the activity of Jumonji demethylases without affecting other α-ketoglutarate dependent hydroxylases or histone modifying enzymes.[3]
JIB-04 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Nalm6 cells
0.5 µM
24 hours
JIB-04 increased G9a methylation
Cell Death Dis. 2018 Oct 10;9(10):1038.
U1/HIV cells
0.25-1 µM
JIB-04 treatment increased HIV-1 Gag mRNA level
Nucleic Acids Res. 2019 Aug 22;47(14):7333-7347.
H358 non-small cell lung cancer cells
500 nM
24 hours
JIB-04 E-isomer specifically upregulates anti-growth genes and downregulates pro-growth genes in H358 cells, while no similar changes were observed in normal cells.
Nat Commun. 2013;4:2035.
HCC4017 non-small cell lung cancer cells
0.5 µM
24 hours
JIB-04 E-isomer increased H3K4me3 levels at the c10orf10 promoter in HCC4017 cells.
Nat Commun. 2013;4:2035.
LN229 cells
0.1735 µM
24, 48, 72, 96 hours
JIB-04 inhibited the proliferation of LN229 cells in a dose-dependent manner.
Neuro Oncol. 2024 Apr 5;26(4):653-669.
GBM#P3 cells
1.534 µM
24, 48, 72, 96 hours
JIB-04 inhibited the proliferation of GBM#P3 cells in a dose-dependent manner.
Neuro Oncol. 2024 Apr 5;26(4):653-669.
SCLC cell lines
0.04 µM to 0.49 µM
4 days
JIB-04 significantly decreased the viability of SCLC cell lines, particularly in etoposide-resistant lines
Oncogene. 2024 Sep;43(38):2885-2899.
PC-3 cells
260 nM
48 hours
Evaluate the effect of JIB-04 on PC-3 cells, results showed that JIB-04 decreased EphA2 expression and increased the silencing efficiency of siEphA2.
J Nanobiotechnology. 2021 Mar 8;19(1):71.
DU145 cells
260 nM
48 hours
Evaluate the effect of JIB-04 on DU145 cells, results showed that JIB-04 decreased EphA2 expression and increased the silencing efficiency of siEphA2.
J Nanobiotechnology. 2021 Mar 8;19(1):71.
Nalm6 cells
0.25 µM
72 hours
JIB-04 increased the sensitivity of cells to dexamethasone-induced cell death
Cell Death Dis. 2018 Oct 10;9(10):1038.
J-LAT A2 cells
1 µM
JIB-04 treatment increases the local H3K36me3 level at LTR nuc-1
Nucleic Acids Res. 2019 Aug 22;47(14):7333-7347.
J-LAT 10.6 cells
0.25–1 µM
JIB-04 treatment increased the percentage of GFP-positive cells
Nucleic Acids Res. 2019 Aug 22;47(14):7333-7347.
J89GFP cells
0.25–1 µM
JIB-04 treatment increased the percentage of GFP-positive cells
Nucleic Acids Res. 2019 Aug 22;47(14):7333-7347.
A549 cells
25 nM
4 hours
To evaluate the effect of JIB-04 on radiosensitivity, results showed that JIB-04 significantly increased the intrinsic radiosensitivity of these radioresistant cell lines
Cell Rep. 2018 Oct 23;25(4):1040-1050. e5
H1299 cells
16 nM
4 hours
To evaluate the effect of JIB-04 on radiosensitivity, results showed that JIB-04 significantly increased the intrinsic radiosensitivity of these radioresistant cell lines
Cell Rep. 2018 Oct 23;25(4):1040-1050. e5
JIB-04 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
H358 and A549 lung cancer xenograft models
Intraperitoneal injection or Oral
110 mg/kg (IP) or 55 mg/kg (oral)
2–3 times weekly for 5 weeks
JIB-04 significantly inhibited the growth of H358 and A549 tumors and reduced tumor burden, while showing no significant effects on body weight or overall health of the mice.
Nat Commun. 2013;4:2035.
Nude mice
SCLC tumor xenograft model
Oral
75 mg/kg
Three times a week, for several weeks
JIB-04 significantly inhibited the growth of SCLC tumor xenografts, with reduced tumor volume and weight
Oncogene. 2024 Sep;43(38):2885-2899.
Nude mice
Subcutaneous tumor model of H1299 cells
Oral gavage
50 mg/kg/day
Every other day for a total of 12 doses
To evaluate the effect of combined JIB-04 and radiation therapy on tumor growth and survival, results showed that the combination significantly inhibited tumor growth and prolonged survival
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