A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.
A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.
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DOI：
10.1002/cmdc.201300428
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发表时间：
2014-03
期刊：
影响因子：
3.4
通讯作者：
Kawamura A
中科院分区：
文献类型：
--
作者：
Schiller R;Scozzafava G;Tumber A;Wickens JR;Bush JT;Rai G;Lejeune C;Choi H;Yeh TL;Chan MC;Mott BT;McCullagh JS;Maloney DJ;Schofield CJ;Kawamura A
2-氧戊二酸（2OG）依赖性巨蒙基C域（JmjC）家族是最大的组蛋白赖氨酸去甲基化酶家族。人们有兴趣开发调节JmjC活性的小分子探针来研究它们的生物学作用。5-羧基-8-羟基喹啉（IOX1）是迄今为止报道的最有效的2OG加氧酶的广谱抑制剂，包括JmjC去甲基化酶；然而，它的细胞渗透性低。在这里，我们描述了结构-活性关系研究，导致发现IOX1的正辛酯形式具有提高的细胞效力（EC50值为100至4 μm）。这些发现得到了体外抑制和选择性研究、对接研究、细胞培养活性与毒性分析以及细胞内摄取测量的支持。正辛酯具有改善细胞通透性的作用；发现它以完整的酯形式抑制一些JmjC去甲基化酶，并且比IOX1更具选择性。IOX1的正辛酯应该作为开发JmjC抑制剂的起点，并作为研究2g加氧酶在表观遗传调控中的作用的细胞渗透性工具化合物。
The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure–activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4 μm). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.