2014
Prusevich, Polina; Kalin, Jay H; Ming, Shonoi A; Basso, Manuela; Givens, Jeffrey; Li, Xin; Hu, Jianfei; Taylor, Martin S; Cieniewicz, Anne M; Hsiao, Po-Yuan; Huang, Rong; Roberson, Heather; Adejola, Nkosi; Avery, Lindsay B; Casero, Robert A; Taverna, Sean D; Qian, Jiang; Tackett, Alan J; Ratan, Rajiv R; McDonald, Oliver G; Feinberg, Andrew P; Cole, Philip A
A selective phenelzine analogue inhibitor of histone demethylase LSD1 Journal Article
In: ACS Chem Biol, vol. 9, no. 6, pp. 1284-93, 2014, ISSN: 1554-8937.
Abstract | Links | BibTeX | Tags: Animals, Blotting, Cell Survival, Cells, Cultured, DNA Methylation, Embryo, Enzyme Inhibitors, Fetus, Histone Demethylases, Histones, Humans, Mammalian, Monoamine Oxidase, Neurons, Phenelzine, Rats, Sprague-Dawley, Western
@article{1299983,
title = {A selective phenelzine analogue inhibitor of histone demethylase LSD1},
author = {Polina Prusevich and Jay H Kalin and Shonoi A Ming and Manuela Basso and Jeffrey Givens and Xin Li and Jianfei Hu and Martin S Taylor and Anne M Cieniewicz and Po-Yuan Hsiao and Rong Huang and Heather Roberson and Nkosi Adejola and Lindsay B Avery and Robert A Casero and Sean D Taverna and Jiang Qian and Alan J Tackett and Rajiv R Ratan and Oliver G McDonald and Andrew P Feinberg and Philip A Cole},
doi = {10.1021/cb500018s},
issn = {1554-8937},
year = {2014},
date = {2014-06-01},
journal = {ACS Chem Biol},
volume = {9},
number = {6},
pages = {1284-93},
abstract = {Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.},
keywords = {Animals, Blotting, Cell Survival, Cells, Cultured, DNA Methylation, Embryo, Enzyme Inhibitors, Fetus, Histone Demethylases, Histones, Humans, Mammalian, Monoamine Oxidase, Neurons, Phenelzine, Rats, Sprague-Dawley, Western},
pubstate = {published},
tppubtype = {article}
}
Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.