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]
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