Biochemical, Structural, and Biological Evaluation of Tranylcypromine Derivatives as Inhibitors of Histone Demethylases LSD1 and LSD2
Biochemical, Structural, and Biological Evaluation of Tranylcypromine Derivatives as Inhibitors of Histone Demethylases LSD1 and LSD2
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DOI：
10.1021/ja101557k
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发表时间：
2010-05-19
影响因子：
15
通讯作者：
Mai, Antonello
中科院分区：
文献类型：
--
作者：
Binda, Claudia;Valente, Sergio;Mai, Antonello
LSD 1和LSD 2组蛋白去甲基化酶与许多生理和病理过程有关，从肿瘤发生到疱疹病毒感染。一个全面的结构，生物化学和细胞的研究，在这里探测这些酶的表观遗传疗法的潜力。这种方法采用反苯环丙胺作为化学支架的设计新的去甲基酶抑制剂。该药是一种临床验证的抗抑郁药，已知靶向单胺氧化酶A和B。这两种黄素酶在结构上与LSD 1和LSD 2相关。反苯环丙胺抑制的机制和晶体学研究揭示了缺乏选择性和不同的共价修饰的FAD辅因子取决于对映体形式。这些发现是不相关的，因为反苯环丙胺目前作为外消旋混合物给药。大量的反苯环丙胺类似物的合成和筛选的抑制活性。我们发现，共同的进化起源的LSD和MAO酶，尽管它们不相关的功能和底物特异性，是反映在相关的配体结合特性。鉴定了几个具有部分酶选择性的化合物。使用选择的急性早幼粒细胞白血病细胞模型评估了这些新抑制剂之一的生物活性，因为其发病机制包括几种染色质修饰剂的异常活性。观察到对细胞分化的显著作用和与抗白血病药物的前所未有的协同活性。这些数据表明，这些LSD 1/2抑制剂对于治疗早幼粒细胞白血病具有潜在的相关性，并且更一般地，作为改变染色质状态的工具，有望阻断肿瘤进展。
LSD1 and LSD2 histone demethylases are implicated in a number of physiological and pathological processes, ranging from tumorigenesis to herpes virus infection. A comprehensive structural, biochemical, and cellular study is presented here to probe the potential of these enzymes for epigenetic therapies. This approach employs tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. This drug is a clinically validated antidepressant known to target monoamine oxidases A and B. These two flavoenzymes are structurally related to LSD1 and LSD2. Mechanistic and crystallographic studies of tranylcypromine inhibition reveal a lack of selectivity and differing covalent modifications of the FAD cofactor depending on the enantiomeric form. These findings are pharmacologically relevant, since tranylcypromine is currently administered as a racemic mixture. A large set of tranylcypromine analogues were synthesized and screened for inhibitory activities. We found that the common evolutionary origin of LSD and MAO enzymes, despite their unrelated functions and substrate specificities, is reflected in related ligand-binding properties. A few compounds with partial enzyme selectivity were identified. The biological activity of one of these new inhibitors was evaluated with a cellular model of acute promyelocytic leukemia chosen since its pathogenesis includes aberrant activities of several chromatin modifiers. Marked effects on cell differentiation and an unprecedented synergistic activity with antileukemia drugs were observed. These data demonstrate that these LSD1/2 inhibitors are of potential relevance for the treatment of promyelocytic leukemia and, more generally, as tools to alter chromatin state with promise of a block of tumor progression.