Related Experiment Video

Updated: Jun 12, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

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

Mingwei Fu1, Yuanjiang Wang2, Min Ge3

  • 1Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China; Zenji Research Laboratories, Nanjing 211189, PR China.

Bioorganic & Medicinal Chemistry Letters
|September 18, 2024
PubMed

Insights

New PROTAC compounds targeting Enhancer of zeste homolog 2 (EZH2) were developed. Compound ZJ-20 effectively degraded the PRC2 complex in cancer cells, showing promise as a lead for improved cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Enhancer of zeste homolog 2 (EZH2) is a key histone methyltransferase in cancer biology.
  • Current EZH2 inhibitors exhibit limited clinical efficacy.

Purpose of the Study:

  • To design and synthesize novel EZH2-targeted Proteolysis Targeting Chimeras (PROTACs).
  • To improve upon the limitations of existing EZH2 inhibitors.

Main Methods:

  • PROTAC compounds were designed using Tazemetostat as the protein of interest (POI) ligand.
  • Various linkers were employed in the PROTAC design.
  • In vitro efficacy and pharmacokinetic properties were evaluated.

Main Results:

  • Compound ZJ-20 demonstrated potent activity with an IC50 of 5.0 nM against MINO cells.
  • ZJ-20 exhibited favorable pharmacokinetic parameters.
  • ZJ-20 successfully induced degradation of the PRC2 complex by targeting EZH2.

Conclusions:

  • ZJ-20 represents a promising lead compound for developing next-generation EZH2-targeting cancer therapeutics.
  • PROTAC technology offers a viable strategy to overcome EZH2 inhibitor limitations.
Keywords:
Anti-tumorEZH2Protein degradationProteolysis targeting chimerasTazemetostat

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