Histone methylation is a key epigenetic marker involved in tumorigenesis. The overexpression of histone lysine demethylase KDM4 has been observed in multiple human cancer. NCGC00244536 is a novel, potent KDM4 inhibitor with an IC50 value of 10 nM. It showed a high selective inhibitory effect on the fast-growing AR-negative PC3 cells with an IC50 value of 40 nM. It potently inhibited AR-positive LNCaP and VCaP cell lines with IC50 values less than 1 μM. It also impeded the growth of breast cancer cell lines MDA-MB2 and MCF-7 with IC50 values in the micromolar range. Treatment of LNCaP and PC3 cells with 1 μM NCGC00244536 decreased the number of S phase cells. In SCID mice, daily treatment with 20 mg/kg NCGC00244536 significantly inhibited the tumor growth as compared to the vehicle-treated group without causing any major toxicity. Tumors harvested from NCGC00244536-treated mice showed a significant amount of cell necrosis, apoptosis, and fibrosis[1].
作用机制
NCGC00244536 is a potent KDM4 inhibitor. It specifically binds to the domain of KDM4s, significantly suppressing the binding of KDM4B to the promoter or enhancer regions of target genes.
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