Exploration of Novel Small Molecule Phenelzine Analogue LSD1 Inhibitors

Lysine Specific Demethylase 1;LSD1;phenelzine;bizine;inhibitor;not listed

Prusevich, PolinaCole, Philip A. ;

Johns Hopkins University

关键词: Lysine Specific Demethylase 1;    LSD1;    phenelzine;    bizine;    inhibitor;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37143/PRUSEVICH-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

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. We designed and synthesized analogues of a monoamine oxidase antidepressant, phenelzine, and tested for 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 homolog, 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. Additionally, treatment of cancer cell lines 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. Ultimately, this work produced a potent and selective phenelzine analogue that is a useful probe in the continuing study of LSD1’s demethylase activity in both physiologic and pathophysiologic conditions.