Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
J Med Chem. 2014 Jan 9;57(1):42-55. doi: 10.1021/jm4012802. Epub 2013 Dec 19.
In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed and colocalize with the androgen receptor. We designed and synthesized hybrid LSD1/JmjC or "pan-KDM" inhibitors 1-6 by coupling the skeleton of tranylcypromine 7, a known LSD1 inhibitor, with 4-carboxy-4'-carbomethoxy-2,2'-bipyridine 8 or 5-carboxy-8-hydroxyquinoline 9, two 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds 1-6 are able to simultaneously target both KDM families and have been validated as potential antitumor agents in cells. Among them, 2 and 3 increase H3K4 and H3K9 methylation levels in cells and cause growth arrest and substantial apoptosis in LNCaP prostate and HCT116 colon cancer cells. When tested in noncancer mesenchymal progenitor (MePR) cells, 2 and 3 induced little and no apoptosis, respectively, thus showing cancer-selective inhibiting action.
在前列腺癌中，两种不同类型的组蛋白赖氨酸去甲基酶（KDM），LSD1/KDM1 和 JMJD2/KDM4，与雄激素受体共表达和共定位。我们通过将曲奈普汀 7 的骨架与 4-羧基-4'-羧甲基-2,2'-联吡啶 8 或 5-羧基-8-羟基喹啉 9 偶联，设计并合成了混合 LSD1/JmjC 或“泛 KDM”抑制剂 1-6，后两者是为 JmjC 抑制开发的 2-氧戊二酸竞争模板。混合化合物 1-6 能够同时靶向两个 KDM 家族，并已在细胞中验证为潜在的抗肿瘤剂。其中，2 和 3 增加了细胞中 H3K4 和 H3K9 的甲基化水平，并导致 LNCaP 前列腺和 HCT116 结肠癌细胞的生长停滞和大量细胞凋亡。在非癌性间充质祖细胞（MePR）细胞中进行测试时，2 和 3 分别诱导很少和没有细胞凋亡，因此显示出癌症选择性抑制作用。
