Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
J Med Chem. 2021 Oct 28;64(20):15170-15188. doi: 10.1021/acs.jmedchem.1c01154. Epub 2021 Oct 19.
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 () 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 . In the biochemical assay, inhibited EZH2 (IC = 26.1 nM) with high selectivity over other histone methyltransferases. It was also potent against EZH2 mutants (EZH2 Y641F, IC = 72.3 nM). Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC > 30 μM). In vivo, exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 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.
增强子结合锌指蛋白 2 同源物（EZH2）是多梳抑制复合物 2 的催化亚基，能够催化组蛋白 H3 赖氨酸 27（H3K27）的甲基化。在血液恶性肿瘤和实体瘤中已经鉴定出 EZH2 的过表达或突变。基于 EPZ6438（）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。在酶和细胞水平的结构-活性关系（SAR）探索导致了抑制剂的发现。在生化测定中，对 EZH2（IC = 26.1 nM）具有高选择性，而对其他组蛋白甲基转移酶没有明显的抑制作用。它对 EZH2 突变体（EZH2 Y641F，IC = 72.3 nM）也很有效。此外，它对人 ether-á-go-go 相关基因（hERG）没有明显的抑制活性（IC > 30 μM）。在体内，能够口服给药，具有良好的药代动力学特性，在 Pfeiffer 和 Karpas-422 细胞介导的异种移植小鼠模型中比有效，表明它可能是 EZH2 突变癌症的一种新的潜在治疗候选物。
