2. Academic Validation
  3. Chemically induced degradation of PRC2 complex by EZH2-Targeted PROTACs via a Ubiquitin-Proteasome pathway

Chemically induced degradation of PRC2 complex by EZH2-Targeted PROTACs via a Ubiquitin-Proteasome pathway

  • Bioorg Med Chem Lett. 2024 Nov 15:113:129968. doi: 10.1016/j.bmcl.2024.129968.
Mingwei Fu 1,  Yuanjiang Wang 2,  Min Ge 3,  Chunchen Hu 3,  Ya Xiao 3,  Yan Ma 3,  Shaohua Gou 4
Affiliations

Affiliations

  • 1 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China; Zenji Research Laboratories, Nanjing 211189, PR China.
  • 2 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
  • 3 Zenji Research Laboratories, Nanjing 211189, PR China.
  • 4 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China. Electronic address: sgou@seu.edu.cn.
PMID: 39293534 DOI: 10.1016/j.bmcl.2024.129968
Abstract

Enhancer of zeste homolog 2 (EZH2) is a Histone Methyltransferase that plays an important role in Cancer cells biology. However, present EZH2 inhibitors in clinic have not achieved satisfactory efficacy. Herein, a number of EZH2-targeted PROTAC compounds were designed and synthesized by selecting different linkers, using Tazemetostat as the protein of interest (POI) portion of PROTAC molecules, hoping to improve the defects of existing EZH2 inhibitors effectively. Among all the target compounds, ZJ-20 showed the best performance with an IC50 value of 5.0 nM against MINO cells, good pharmacokinetics parameters and a limited acceptable oral bioavailability. Significantly, ZJ-20 could achieve degradation of the entire PRC2 complex by targeting EZH2, which can serve as a lead compound for further study.

Keywords

Anti-tumor; EZH2; Protein degradation; Proteolysis targeting chimeras; Tazemetostat.

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