Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the "tail" region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.

中文翻译：

---

（E）-1,2-二苯乙烯基EZH2抑制剂的设计与合成。

zeste同源物2（EZH2）的增强子是多梳抑制复合物2（PRC2）的催化亚基，与癌症进展转移和不良预后有关。基于具有低纳摩尔活性的EZH2抑制剂SKLB1049，我们扩展了“尾巴”区域，获得了一系列作为新型EZH2抑制剂的（E）-1,2-二苯乙烯衍生物。SAR探索和初步评估导致发现了有效的新型EZH2抑制剂9b（EZH2WT IC50 = 22.0 nM）。化合物9b抑制WSU-DLCL2和SU-DHL-4细胞系的增殖（IC50分别为1.61 µM和2.34 µM）。生物学评估表明，9b是野生型EZH2的有效抑制剂，并以浓度依赖的方式大大降低了H3K27me3的总体水平。进一步的研究表明9b可以显着诱导SU-DHL-4细胞凋亡。这些发现表明9b将是用于进一步优化和评估的有吸引力的先导化合物。