Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: A novel class of irreversible inhibitors of histone demethylase KDM1A
Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: A novel class of irreversible inhibitors of histone demethylase KDM1A
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DOI：
10.1016/j.ejmech.2014.08.068
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发表时间：
2014-10-30
影响因子：
6.7
通讯作者：
Mercurio, Ciro
中科院分区：
文献类型：
--
作者：
Vianello, Paola;Botrugno, Oronza A.;Mercurio, Ciro
组蛋白去甲基化酶KDM 1A（也称为LSD 1）已成为治疗癌症以及病毒感染等其他疾病的有吸引力的治疗靶点。我们报告的化合物的合成来自反苯环丙胺作为化学支架的设计新的去甲基酶抑制剂的扩展。评价了这些在环丙基核心部分上被取代的化合物在体外抑制KDM 1A的能力以及通过调节公认的KDM 1A靶基因Gfi-1b的表达在细胞中发挥功能的能力。发现这些分子均共价抑制KDM 1A，并且通过在环丙胺环上引入更大的取代基，对人单胺氧化酶MAO A和MAO B的选择性增加。对所选反式异构体的结构和生化分析表明，这两种立体异构体对KDM 1A具有相似的抑制活性，但与FAD辅酶形成不同的共价加合物。(C)2014年Elsevier Masson SAS。All rights reserved.
Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme. (C) 2014 Elsevier Masson SAS. All rights reserved.