The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been identified in hematologic malignancies and solid tumors. Based on the structure of EPZ6438 (1) and the binding model with PRC2, we designed a series of analogues aiming to improve the activities of EZH2 mutants. Structure–activity relationship (SAR) exploration at both enzymatic and cellular levels led to the discovery of inhibitor 29. In the biochemical assay, 29 inhibited EZH2 (IC₅₀ = 26.1 nM) with high selectivity over other histone methyltransferases. It was also potent against EZH2 mutants (EZH2 Y641F, IC₅₀ = 72.3 nM). Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC₅₀ > 30 μM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 1 in both Pfeiffer and Karpas-422 cell-mediated xenograft mouse models, indicating that it might be a new potential therapeutic candidate for EZH2 mutant cancers.

中文翻译：

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发现 IHMT-EZH2-115 作为 Zeste 同源物 2 (EZH2) 抑制剂的强效选择性增强剂治疗 B 细胞淋巴瘤

zeste 同源物 2 (EZH2) 的增强子是多梳抑制复合物 2 的催化亚基，可催化组蛋白 H3 赖氨酸 27 (H3K27) 的甲基化。已经在血液系统恶性肿瘤和实体瘤中发现了 EZH2 的过度表达或突变。基于EPZ6438( 1 )的结构和与PRC2的结合模型，我们设计了一系列旨在提高EZH2突变体活性的类似物。在酶促和细胞水平上的构效关系 (SAR) 探索导致了抑制剂29的发现。在生化测定中，29抑制 EZH2 (IC ₅₀ = 26.1 nM)，其选择性高于其他组蛋白甲基转移酶。它还对 EZH2 突变体（EZH2 Y641F，IC ₅₀= 72.3 nM)。此外，它对人ether-á-go-go相关基因（hERG）没有表现出明显的抑制活性（IC ₅₀ > 30 μM）。在体内，29表现出良好的口服药代动力学特性，并且在 Pfeiffer 和 Karpas-422 细胞介导的异种移植小鼠模型中表现出比1更好的疗效，表明它可能是 EZH2 突变癌症的新潜在治疗候选者。