Design, Synthesis, Enzyme-Inhibitory Activity, and Effect on Human Cancer Cells of a Novel Series of Jumonji Domain-Containing Protein 2 Histone Demethylase Inhibitors
Design, Synthesis, Enzyme-Inhibitory Activity, and Effect on Human Cancer Cells of a Novel Series of Jumonji Domain-Containing Protein 2 Histone Demethylase Inhibitors
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DOI：
10.1021/jm1003655
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发表时间：
2010-08-12
影响因子：
7.3
通讯作者：
Miyata, Naoki
中科院分区：
文献类型：
--
作者：
Hamada, Shohei;Suzuki, Takayoshi;Miyata, Naoki
含Jumonji结构域蛋白（JMJD）组蛋白去甲基化酶的选择性抑制剂是候选的抗癌药物，也是阐明JMJD生物学功能的潜在工具。根据JMJD 2A的晶体结构和JMJD 2C的同源模型，我们设计并合成了一系列带有叔胺的异羟肟酸类似物。使用JMJD 2C、JMJD 2A和脯氨酰羟化酶的酶测定显示，异羟肟酸类似物8是有效的和选择性的JMJD 2抑制剂，与先导化合物N-草酰甘氨酸2相比，显示出500倍的JMJD 2C抑制活性和超过9100倍的JMJD 2C选择性。化合物17和18（化合物8的前药）各自与赖氨酸特异性脱甲基酶I（LSD 1）的抑制剂组合显示出对癌细胞的协同生长抑制。这些发现表明，JMJD 2抑制剂和LSD I抑制剂的组合治疗可能代表抗癌化疗的新策略。
Selective inhibitors of Jumonji domain-containing protein (JMJD) histone demethylases are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs. On the basis of the crystal structure of JMJD2A and a homology model of JMJD2C, we designed and prepared a series of hydroxamate analogues bearing a tertiary amine. Enzyme assays using JMJD2C, JMJD2A, and prolyl hydroxylases revealed that hydroxamate analogue 8 is a potent and selective JMJD2 inhibitor, showing 500-fold greater JMJD2C-inhibitory activity and more than 9100-fold greater JMJD2C-selectivity compared with the lead compound N-oxalylglycine 2. Compounds 17 and 18, prodrugs of compound 8, each showed synergistic growth inhibition of cancer cells in combination with an inhibitor of lysine-specific demethylase I (LSD1). These findings suggest that combination treatment with JMJD2 inhibitors and LSD I inhibitors may represent a novel strategy for anticancer chemotherapy.