As a master regulator of chromatin function, the lysine methyltransferase EZH2 (enhancer of zeste homologue 2) orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC). JQEZ5 is a novel and potent EZH2 inhibitor which shows antitumor efficacy. Human oncogene wild-type NSCLC cells H661 treated with increasing concentrations of JQEZ5 demonstrated acutely reduced levels of H3K27me3, which prompted silencing of tumor suppressors and developmental regulators and was associated with over-expression of EZH2. This assay supported the notion that JQEZ5 was effectively targeting EZH2 in human lung cancer cell lines. Tumor-bearing mice treated with JQEZ5 for three weeks (75 mg/kg intraperitoneal (IP) daily) exhibited rapid and pronounced tumor regression over the three week treatment course. Additionally, H3K27me3 levels were largely reduced with treatment further confirming the on-target effect of JQEZ5 in mice [1].
作用机制
D-pyridinone ring of JQEZ5 binds to Asn78 on EZH2, and that the pyrazolo-pyridine ring is deeply buried in the S-adenosyl methionine (SAM)-binding pocket of EZH2 .
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