2. Academic Validation
  3. Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2

Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2

  • J Med Chem. 2021 Mar 11;64(5):2829-2848. doi: 10.1021/acs.jmedchem.0c02234.
Zhihao Liu 1,  Xi Hu 1,  Qiwei Wang 1,  Xiuli Wu 1,  Qiangsheng Zhang 1,  Wei Wei 1,  Xingping Su 1,  Hualong He 1,  Shuyan Zhou 1,  Rong Hu 2,  Tinghong Ye 1,  Yongxia Zhu 3,  Ningyu Wang 2,  Luoting Yu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 2 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
  • 3 Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
PMID: 33606537 DOI: 10.1021/acs.jmedchem.0c02234
Abstract

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for Anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various Cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against Cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

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