期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 17, 页码 7378-7391出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3002845
关键词
-
资金
- NIH grant [1R01CA149095, 1RO1CA98454, IRO1CA51085]
- Samuel Waxman Cancer Research Foundation
- Susan B. Komen for the Cure Foundation
- Progen Pharmaceuticals, Ltd., Brisbane, Queensland, Australia
- EPSCoR
- Office Of The Director [919440] Funding Source: National Science Foundation
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据