Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure–activity relationship at enzymatic and cellular levels, compound was identified. Biochemical assays showed that compound (IC = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with (IC = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC = 0.03 nM; EZH2 Y641N, IC = 0.08 nM), which were approximately 10-fold more active than those of (EZH2 Y641F, IC = 0.37 nM; EZH2 Y641N, IC = 0.85 nM). Furthermore, compound (IC = 3.52 ± 1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than (IC = 35.01 ± 1.28 nM). Further cellular experiments showed that arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, (T = 177.69 min) showed improved metabolic stability in human liver microsomes compared with (T = 7.97 min). Our findings suggest as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop .

中文翻译：

---

发现具有 1-甲基-2-苯并咪唑啉酮部分的新型吡啶酮-苯甲酰胺衍生物作为有效的 EZH2 抑制剂，用于治疗 B 细胞淋巴瘤

zeste 同源物增强子 2 (EZH2) 是弥漫性大 B 细胞淋巴瘤的一个有前景的治疗靶点。在本研究中，基于（tazemetostat）与多梳抑制复合物2（PRC2）的结合模型，我们设计并合成了一系列带有1-甲基-2-苯并咪唑啉酮部分的tazemetostat类似物，以提高EZH2野生型的抑制活性。型 (WT) 和 Y641 突变体并增强代谢稳定性。在酶和细胞水平评估结构-活性关系后，鉴定出化合物。生化检测表明，与 (IC = 1.20 nM) 相比，化合物 (IC = 0.32 nM) 对 EZH2 WT 表现出优异的抑制活性，并且对 EZH2 Y641 突变体 (EZH2 Y641F，IC = 0.03 nM；EZH2 Y641N，IC = 0.08) 具有高效力。 nM)，其活性比 (EZH2 Y641F，IC = 0.37 nM；EZH2 Y641N，IC = 0.85 nM) 的活性高约 10 倍。此外，化合物 (IC50 = 3.52 ± 1.23 nM) 可有效抑制 Karpas-422 细胞的增殖，并且比 (IC50 = 35.01 ± 1.28 nM) 更有效。进一步的细胞实验表明，将 Karpas-422 细胞阻滞在 G1 期，并以剂量​​依赖性方式诱导细胞凋亡。此外，在携带 EZH2 Y641N 突变体的 Karpas-422 细胞中，抑制组蛋白 H3 (H3K27Me3) 上赖氨酸 27 的三甲基化。此外，与（T = 7.97 分钟）相比，（T = 177.69 分钟）显示人肝微粒体的代谢稳定性有所改善。我们的研究结果表明，EZH2 是一种很有前景的抑制剂；仍有必要进行进一步调查以确认我们的调查结果并进一步发展。