Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1-specific inhibitors have been pursued. Trans-2-phenylcyclopropylamine (2-PCPA)-based inhibitors featuring substitutions on the amino group have emerged, with sub-micromolar affinities toward LSD1 and high selectivities over monoamine oxidases (MAOs). We synthesized two N-alkylated 2-PCPA-based LSD1 inhibitors, S2116 and S2157, based on the previously developed S2101. S2116 and S2157 exhibited enhanced potency for LSD1 by 2.0- to 2.6-fold, as compared with S2101. In addition, they exhibited improved selectivity over MAOs. Structural analyses of LSD1 co-crystallized with S2101, S2116, S2157, or another N-alkylated inhibitor (FCPA-MPE) confirmed that the N-substituents enhance the potency of a 2-PCPA-based inhibitor of LSD1, without constituting the adduct formed with FAD.

中文翻译：

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N-烷基化的反式-2-苯基环丙胺基LSD1抑制剂的开发和结构评价。

赖氨酸特异性脱甲基酶1（LSD1）是黄素腺嘌呤二核苷酸（FAD）依赖性酶，可催化组蛋白H3的脱甲基化并调节基因表达。由于它与疾病的调控有关，例如急性髓细胞性白血病，因此一直在寻求有效的LSD1特异性抑制剂。以氨基取代为特征的基于反式-2-苯基环丙胺（2-PCPA）的抑制剂已经出现，对LSD1具有亚微摩尔亲和力，对单胺氧化酶（MAO）具有高选择性。基于以前开发的S2101，我们合成了两种基于N-烷基化的2-PCPA的LSD1抑制剂S2116和S2157。与S2101相比，S2116和S2157对LSD1的效力提高了2.0到2.6倍。另外，它们表现出比MAO更高的选择性。与S2101，S2116共结晶的LSD1的结构分析