Zhou Chao, Wu Fangrui, Lu Lianghao, Wei Liping, Pai Eric, Yao Yuan, Song Yongcheng
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
PLoS One. 2017 Feb 3;12(2):e0170301. doi: 10.1371/journal.pone.0170301. eCollection 2017.
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B. Several cyclopropylamine containing compounds were found to be highly potent and selective inhibitors of LSD1. A novel series cyclopropylimine compounds also exhibited strong inhibitory activity against LSD1. Structure activity relationships (SAR) of these compounds are discussed. Docking studies were performed to provide possible binding models of a representative compound in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity.
组蛋白的翻译后修饰在基因转录中发挥着重要作用。组蛋白赖氨酸侧链的异常甲基化在癌症中经常被发现。赖氨酸特异性去甲基化酶1（LSD1）能够使组蛋白H3赖氨酸4（H3K4）及其他蛋白质去甲基化，最近它被发现是急性髓性白血病的一个药物靶点。为了了解LSD1抑制剂的构效/选择性关系，合成了几个系列的环丙胺及相关化合物，并测试了它们对LSD1以及相关单胺氧化酶（MAO）A和B的活性。发现几种含环丙胺的化合物是LSD1的高效且选择性抑制剂。一个新的环丙亚胺化合物系列也表现出对LSD1的强抑制活性。讨论了这些化合物的构效关系（SAR）。进行了对接研究以提供一种代表性化合物在LSD1和MAO-A中的可能结合模型。此外，这些建模研究可以解释观察到的构效关系和选择性。
