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. 2023 Nov:140:106762.
doi: 10.1016/j.bioorg.2023.106762. Epub 2023 Aug 8.

Design, synthesis and evaluation of EZH2-based PROTACs targeting PRC2 complex in lymphoma

Huiru Xie  1 , Wei Xu  2 , Jing Liang  3 , Yang Liu  3 , Chenxi Zhuo  2 , Xiaoxue Zou  2 , Weihong Luo  2 , Jianping Xiao  4 , Yu Lin  5 , Lixia Chen  6 , Hua Li  7
Affiliations

Design, synthesis and evaluation of EZH2-based PROTACs targeting PRC2 complex in lymphoma

Huiru Xie et al. Bioorg Chem. 2023 Nov.

Abstract

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.

Keywords: Anti-proliferative activity; EPZ6438; EZH2 degradation; PROTAC.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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