Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1

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关键作用。组蛋白赖氨酸侧链的异常甲基化常见于癌症中。赖氨酸特异性去甲基化酶1（Lysine specific demethylase 1, LSD1）可对组蛋白H3赖氨酸4（H3K4）及其他蛋白进行去甲基化，近期被发现是急性髓系白血病的药物靶点。为阐明LSD1抑制剂的构效/选择性关系，研究人员合成了多系列环丙胺及其相关化合物，并测试了它们针对LSD1以及单胺氧化酶（MAO）A和B的活性。研究发现多款含环丙胺结构的化合物对LSD1具有高效且选择性的抑制作用。一类新型环丙亚胺化合物同样展现出对LSD1的强抑制活性。本文对这些化合物的构效关系（SAR）进行了讨论。通过分子对接研究，得到了代表性化合物在LSD1和MAO-A中的潜在结合模型。此外，这些建模研究可合理解释所观测到的构效关系与选择性特征。