Department of Pharmacology, ∥Center for Epigenetics and Department of Medicine, ⊥Department of Ophthalmology, and ¶The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
ACS Chem Biol. 2014 Jun 20;9(6):1284-93. doi: 10.1021/cb500018s. Epub 2014 Apr 7.
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.
赖氨酸特异性脱甲基酶 1（LSD1）是一种表观遗传酶，可氧化切割组蛋白 H3 上的单甲基和二甲基赖氨酸 4（H3K4Me1、H3K4Me2）上的甲基基团，有助于基因沉默。本研究描述了单胺氧化酶抗抑郁药苯乙肼类似物的设计和合成及其 LSD1 抑制特性。含有苯丁酰胺附肢的新型苯乙肼类似物（bizine）被证明是一种有效的 LSD1 抑制剂，对单胺氧化酶 A/B 和 LSD1 同源物 LSD2 具有选择性。Bizine 被发现可有效调节癌细胞中大量组蛋白甲基化，ChIP-seq 实验表明，受 bizine 影响的基因和 LSD1-/-细胞中改变的基因的 H3K4 甲基化模式存在统计学显著重叠。Bizine 处理两种癌细胞系 LNCaP 和 H460，可降低增殖率，与测试的五种 HDAC 抑制剂中的两种联合使用时，对细胞生长具有相加至协同作用。此外，暴露于氧化应激的神经元受到 bizine 的保护，这表明其在神经退行性疾病中有潜在的应用。
