Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor 5 displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid 5 impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, 5 hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy.

中文翻译：

---

一流的双重EZH2 / HDAC抑制剂设计：癌细胞的生化活性和生物学评估。

由于组蛋白修饰酶EZH2和HDAC控制许多表观遗传依赖性致癌途径，因此我们设计了同类中第一个双重EZH2 / HDAC抑制剂5，对两个靶标均表现出（亚）微摩尔抑制作用。当在几种癌细胞系中进行测试时，杂合体5在低微摩尔水平以及白血病U937和横纹肌肉瘤RH4细胞中损害了细胞活力，提供了G1阻滞，凋亡诱导和分化增强，并伴有乙酰H3和乙酰α-的增加。微管蛋白和H3K27me3水平降低。在胶质母细胞瘤U87细胞中，有5种通过增加E-钙黏着蛋白的表达而阻碍了上皮向间充质的转化，因此，其自身有望成为抗癌治疗的有用候选药物。