Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Avenue, Detroit, Michigan 48202, USA.
J Med Chem. 2012 Sep 13;55(17):7378-91. doi: 10.1021/jm3002845. Epub 2012 Sep 4.
The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.
最近发现的酶赖氨酸特异性去甲基酶 1（LSD1）在基因表达的表观遗传调控中发挥重要作用，LSD1 失调导致的异常基因沉默被认为有助于癌症的发展。我们曾报道，（双）胍类、（双）脒类及其脲和硫脲类同系物是 LSD1 的有效抑制剂，并在体外诱导肿瘤细胞中异常沉默的肿瘤抑制基因重新表达。我们现在报告了一系列小分子酰胺肟，它们对重组 LSD1 是中等抑制剂，但在 Calu-6 肺癌细胞中，对组蛋白 3 赖氨酸 4（H3K4）染色质标记（LSD1 的特定靶标）的甲基化产生显著变化。此外，这些类似物增加了分泌卷曲相关蛋白（SFRP）2、H-钙粘蛋白（HCAD）和转录因子 GATA4 的细胞内水平。这些化合物代表了一类重要的新型药物样表观遗传调节剂先导化合物，具有作为抗肿瘤药物的潜力。
