Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1
摘要:
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.
SMALL MOLECULES AS EPIGENETIC MODULATORS OF LYSINE-SPECIFIC DEMETHYLASE 1 AND METHODS OF TREATING DISORDERS
申请人:Casero Robert A.
公开号:US20140011857A1
公开(公告)日:2014-01-09
The invention provides for novel compounds which are inhibitors of lysine-specific demethylase 1 (LSD1). Such compounds may be used to treat disorders, including cancer.
US9527805B2
申请人:——
公开号:US9527805B2
公开(公告)日:2016-12-27
[EN] SMALL MOLECULES AS EPIGENETIC MODULATORS OF LYSINE-SPECIFIC DEMETHYLASE 1 AND METHODS OF TREATING DISORDERS<br/>[FR] PETITES MOLÉCULES À TITRE DE MODULATEURS ÉPIGÉNÉTIQUES DE LA DÉMÉTHYLASE 1 SPÉCIFIQUE DE LA LYSINE ET MÉTHODES DE TRAITEMENT DE TROUBLES
申请人:UNIV JOHNS HOPKINS
公开号:WO2012034116A2
公开(公告)日:2012-03-15
The invention provides for novel compounds which are inhibitors of lysine- specific demethylase 1 (LSDl). Such compounds may be used to treat disorders, including cancer.
Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1
作者:Stuart Hazeldine、Boobalan Pachaiyappan、Nora Steinbergs、Shannon Nowotarski、Allison S. Hanson、Robert A. Casero、Patrick M. Woster
DOI:10.1021/jm3002845
日期:2012.9.13
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.