A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

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.

赖氨酸特异性去甲基化酶1（Lysine-specific demethylase 1, LSD1）是一种表观遗传酶，可通过氧化性反应切除组蛋白H3第4位赖氨酸（H3K4Me1、H3K4Me2）上的一甲基与二甲基基团，参与基因沉默过程。
本研究报道了单胺氧化酶抑制剂类抗抑郁药苯乙肼（phenelzine）类似物的设计与合成，及其对LSD1的抑制活性。其中一款带有苯基丁酰胺取代基的新型苯乙肼类似物（bizine）被证实为体外强效LSD1抑制剂，且对单胺氧化酶A/B及LSD1同源蛋白LSD2具有优异选择性。
研究发现，bizine可有效调控癌细胞中的整体组蛋白甲基化水平；染色质免疫共沉淀测序（ChIP-seq）实验结果显示，受bizine调控的基因与LSD1敲除（LSD1–/–）细胞中表达发生改变的基因，其H3K4甲基化模式存在统计学意义上的显著重叠。
用bizine处理LNCaP与H460两种癌细胞系，可显著降低细胞增殖速率；在受试的5种组蛋白去乙酰化酶抑制剂（HDAC inhibitors）中，bizine与其中两种联合使用时，可展现出从相加至协同的细胞生长抑制效应。
此外，bizine可对暴露于氧化应激的神经元起到保护作用，提示其在神经退行性疾病治疗领域具备潜在应用价值。