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The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex

Yupeng He1, Sujatha Selvaraju1, Michael L Curtin1

  • 1AbbVie Inc., North Chicago, Illinois, USA.

Nature Chemical Biology
|January 31, 2017
PubMed

Insights

Researchers identified A-395, a novel drug targeting the EED protein within Polycomb repressive complex 2 (PRC2). This antagonist inhibits epigenetic gene silencing and shows promise against cancer cell lines resistant to other treatments.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • Polycomb repressive complex 2 (PRC2) regulates epigenetic states crucial for development and homeostasis.
  • PRC2 mediates histone H3 lysine 27 trimethylation (H3K27me3), leading to gene silencing, and is implicated in cancer.
  • The embryonic ectoderm development (EED) protein is a key PRC2 subunit with scaffolding and H3K27me3-binding roles.

Purpose of the Study:

  • To identify and characterize a novel antagonist targeting the EED subunit of PRC2.
  • To investigate the mechanism of action and therapeutic potential of this antagonist.

Main Methods:

  • Identification of A-395 as a potent antagonist of EED's H3K27me3-binding function.
  • Structural studies to elucidate the binding mode of A-395 within the EED H3K27me3 pocket.
  • In vitro and in vivo phenotypic analysis of A-395's effects on PRC2 activity and cancer cell lines.

Main Results:

  • A-395 binds to EED, inhibiting allosteric activation of PRC2 catalytic activity.
  • Phenotypic effects of A-395 mimic known PRC2 inhibitors.
  • A-395 demonstrates potent activity against cell lines resistant to catalytic PRC2 inhibitors.

Conclusions:

  • A-395 is a first-in-class antagonist of PRC2 protein-protein interactions (PPI).
  • A-395 serves as a valuable chemical probe for studying EED-containing complexes.
  • This compound offers a new therapeutic strategy for cancers with dysregulated PRC2 activity.

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