Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Aichi, Japan.
J Med Chem. 2010 Aug 12;53(15):5629-38. doi: 10.1021/jm1003655.
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 1 (LSD1). These findings suggest that combination treatment with JMJD2 inhibitors and LSD1 inhibitors may represent a novel strategy for anticancer chemotherapy.
选择性抑制 Jumonji 结构域包含蛋白（JMJD）组蛋白去甲基酶是候选抗癌药物，也是阐明 JMJDs 生物学功能的潜在工具。基于 JMJD2A 的晶体结构和 JMJD2C 的同源模型，我们设计并制备了一系列带有叔胺的偕胺肟类似物。使用 JMJD2C、JMJD2A 和脯氨酰羟化酶进行的酶测定表明，偕胺肟类似物 8 是一种强效和选择性的 JMJD2 抑制剂，与先导化合物 N-草酰基甘氨酸 2 相比，对 JMJD2C 的抑制活性高 500 倍，对 JMJD2C 的选择性高 9100 倍以上。化合物 17 和 18 是化合物 8 的前药，与赖氨酸特异性去甲基酶 1（LSD1）抑制剂联合使用，每种药物都显示出协同抑制癌细胞生长的作用。这些发现表明，JMJD2 抑制剂和 LSD1 抑制剂的联合治疗可能代表一种新的抗癌化疗策略。
