EZH2是PcG成员之一，当其高表达时可以诱导癌症的发生。作为EZH2抑制剂，Tazemetostat （EPZ6438）可以抑制EZH2的甲基化催化活性。然而，许多研究已经表明仅仅抑制EZH2并不能有效地阻断肿瘤的发展。因此，在本研究中，利用蛋白酶靶向嵌合物技术来增强EPZ6438的抗增殖效能，通过降解EZH2的致癌活性。基于VHL、CRBN、MDM2和cIAP E3连接酶系统，已经合成了多个PROTACs，结合EPZ6438和四个E3连接酶配基。在我们的研究中，化合物E-3P-MDM2是最活跃的PROTAC分子。它以浓度和剂量依赖的方式降解了SU-DHL-6细胞中的EZH2，并且还降解了EED和SUZ12蛋白，而不影响它们的mRNA水平，然后显著抑制了H3K27me3的表达。E-3P-MDM2的体外抗增殖活性比EPZ6438要强得多。版权所有 © 2023 Elsevier Inc. 保留所有权利。

EZH2 is a member of PcG and can induce the occurrence of cancer when it is highly expressed. As an EZH2 inhibitor, Tazemetostat (EPZ6438) can inhibit the methylation catalytic activity of EZH2. However, many studies have shown that inhibition of EZH2 alone does not efficiently block tumor development. Therefore, in this study, proteolytic targeting chimera technology was employed to enhance the antiproliferative potency of EPZ6438 by degrading the oncogenic activity of EZH2. Several PROTACs have been synthesized by combining EPZ6438 with four E3 ligase ligands based on VHL, CRBN, MDM2, and cIAP E3 ligase systems. In our study, compound E-3P-MDM2 is the most active PROTAC molecule. It degraded EZH2 of the SU-DHL-6 cells in a concentration and dose-dependent manner and also degraded both EED and SUZ12 protein without affecting their mRNA levels, then significantly inhibited the expression of H3K27me3. The in vitro antiproliferative activity of E-3P-MDM2 was much stronger than that of EPZ6438.Copyright © 2023 Elsevier Inc. All rights reserved.