Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.
Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.
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小分子和组蛋白底物类似物作为LSD1赖氨酸脱甲基酶抑制剂的比较分析。
DOI：
10.1021/ja909996p
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发表时间：
2010-03-10
影响因子：
15
通讯作者：
Cole, Philip A.
中科院分区：
文献类型：
--
作者：
Culhane, Jeffrey C.;Wang, Dongqing;Yen, Paul M.;Cole, Philip A.
LSD1是一种黄素依赖的组蛋白去甲基化酶，它能氧化去除组蛋白H3的赖氨酸 - 4上的甲基。LSD1属于胺氧化酶超家族，该家族利用分子氧将胺转化为亚胺，亚胺再水解裂解为甲醛。在先前的研究中，已经表明单胺氧化酶抑制支架（如炔丙胺和环丙胺）可作为LSD1基于机制的失活剂。炔丙胺 - 组蛋白H3肽类似物是有效的LSD1抑制剂，而小分子抗抑郁药单胺氧化酶（MAO）炔类抑制剂如帕吉林并不抑制LSD1。相反，小分子MAO环丙胺抑制剂反苯环丙胺是一种时间依赖性的LSD1抑制剂，但外 - 环丙胺 - 肽底物类似物则不是。为了进一步深入了解LSD1抑制中
小分子与肽的关系，在此我们进一步分析肽支架中的活性部分，将氯乙烯基、内 - 环丙胺和肼官能团作为LSD1失活剂。我们发现氯乙烯基 - H3是一种基于机制的LSD1失活剂，而内 - 环丙胺 - H3没有显示出时间依赖性失活。肼 - H3被证明是迄今为止报道的最有效的LSD1自杀性抑制剂，在抑制去甲基化方面比炔丙胺 - H3衍生物的效率高20多倍。我们重新探究了MAO抗抑郁药苯乙肼（苯乙基肼），先前报道它是一种弱LSD1抑制剂，并且发现它比之前所认为的要有效得多。我们表明苯乙肼能够阻断细胞中组蛋白H3K4Me的去甲基化，验证了它作为一种药理学工具以及抗癌治疗的潜在先导结构。
LSD1 is a flavin dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily which utilize molecular oxygen to transform amines to imines that are hydrolytically cleaved to formaldehyde. In prior studies, it has been shown that monoamine oxidase inhibitory scaffolds such as propargylamines and cyclopropylamines can serve as mechanism-based inactivators of LSD1. Propargylamine-histone H3 peptide analogs are potent LSD1 inhibitors whereas small molecule antidepressant MAO acetylenic inhibitors like pargyline do not inhibit LSD1. In contrast, the small molecule MAO cyclopropylamine inhibitor tranylcypromine is a time-dependent LSD1 inhibitor but exo-cyclopropylamine-peptide substrate analog is not. To provide further insight into small molecule versus peptide relationships in LSD1 inhibition, herein we further our analysis of warheads in peptide scaffolds to include the chlorovinyl, endo-cyclopropylamine, and hydrazine-functionalities as LSD1 inactivators. We find that chlorovinyl-H3 is a mechanism-based LSD1 inactivator whereas endo-cyclopropylamine-H3 does not show time-dependent inactivation. The hydrazine-H3 was shown to be the most potent LSD1 suicide inhibitor yet reported, more than 20-fold more efficient in inhibiting demethylation than propargylamine-H3 derivatives. We re-explored MAO antidepressant agent phenelzine (phenethylhydrazine), previously reported to be a weak LSD1 inhibitor, and found that it is far more potent than previously appreciated. We show that phenelzine can block histone H3K4Me demethylation in cells, validating it as a pharmacologic tool and potential lead structure for anti-cancer therapy.
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