Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors
Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors
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DOI：
10.1002/cmdc.202000014
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发表时间：
2020-03-30
期刊：
影响因子：
3.4
通讯作者：
Yokoyama, Shigeyuki
中科院分区：
文献类型：
--
作者：
Niwa, Hideaki;Sato, Shin;Yokoyama, Shigeyuki
赖氨酸特异性去甲基化酶1（LSD 1）是一种黄素腺嘌呤二核苷酸（FAD）依赖性酶，催化组蛋白H3的去甲基化并调节基因表达。由于它涉及急性髓性白血病等疾病的调节，因此一直在寻求有效的LSD 1特异性抑制剂。已经出现了基于反式-2-苯基环丙胺（2-PCPA）的抑制剂，其特征在于氨基上的取代，对LSD 1具有亚微摩尔亲和力，并且对单胺氧化酶（MAO）具有高选择性。我们在S2101的基础上合成了两个N-烷基化的2-PCPA基LSD 1抑制剂S2116和S2157。与S2101相比，S2116和S2157对LSD 1的效力提高了2.0- 2.6倍。此外，它们表现出比MAO更高的选择性。与S2101、S2116、S2157或另一种N-烷基化抑制剂（FCPA-MPE）共结晶的LSD 1的结构分析证实，N-取代基增强了基于2-PCPA的LSD 1抑制剂的效力，而不构成与FAD形成的加合物。
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.