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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
Summary
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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