鉴定选择性抑制 PR-SET7 和 EZH2 诱导人白血病 U937 细胞死亡的化合物。
Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells.
机构信息
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le A. Moro 5, 00185 Roma, Italy.
出版信息
Biochimie. 2012 Nov;94(11):2308-13. doi: 10.1016/j.biochi.2012.06.003. Epub 2012 Jun 16.
Chemical manipulations undertaken on some bis(bromo- and dibromo-phenol) compounds previously reported by us as wide-spectrum epigenetic inhibitors let us to identify bis (bromo- and dibromo-methoxyphenyl) derivatives highly selective for PR-SET7 and EZH2 (compounds 4, 5, 9, and 10). Western blot analyses were carried out in U937 cells to determine the effects of such compounds on the methyl marks related to the tested enzymes (H3K4me1, H3K9me2, H4H20me1, and H3K27me3). The 1,5-bis(3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one 4 (EC(50) vs EZH2 = 74.9 μM), tested in U937 cells at 50 μM, induced massive cell death and 28% of granulocytic differentiation, highlighting the potential use of EZH2 inhibitors in cancer.
我们对之前报道的一些双（溴代和二溴代苯酚）化合物进行了化学修饰，这些化合物是我们之前报道的广谱表观遗传抑制剂，使我们能够鉴定出对 PR-SET7 和 EZH2 具有高选择性的双（溴代和二溴代甲氧基苯基）衍生物（化合物 4、5、9 和 10）。在 U937 细胞中进行了 Western blot 分析，以确定这些化合物对测试酶（H3K4me1、H3K9me2、H4H20me1 和 H3K27me3）相关甲基标记的影响。在 50μM 的浓度下，在 U937 细胞中测试的 1,5-双（3-溴-4-甲氧基苯基）戊-1,4-二烯-3-酮 4（EC50 对 EZH2=74.9μM）诱导大量细胞死亡和 28%的粒细胞分化，突出了 EZH2 抑制剂在癌症治疗中的潜在用途。
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