2. Academic Validation
  3. Design, synthesis and evaluation of EZH2-based PROTACs targeting PRC2 complex in lymphoma

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

  • Bioorg Chem. 2023 Nov:140:106762. doi: 10.1016/j.bioorg.2023.106762.
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

Affiliations

  • 1 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
  • 3 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4 The Affiliated Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou 350003, China. Electronic address: 13559168190@139.com.
  • 5 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address: yulam@163.com.
  • 6 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: syzyclx@163.com.
  • 7 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: 2022041@fjtcm.edu.cn.
PMID: 37572533 DOI: 10.1016/j.bioorg.2023.106762
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.

Figures
Products