Rapid Identification of Novel Allosteric PRC2 Inhibitors

Area of Science:

• Epigenetics and chromatin regulation
• Molecular biology and cancer research

Background:

• Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), crucial for histone methylation and gene expression.
• EZH2 dysregulation is implicated in various hematological malignancies and solid cancers.
• Previous high-throughput screening (HTS) for EZH2 inhibitors faced challenges with false positives.

Purpose of the Study:

• To overcome the hit deconvolution challenges in identifying PRC2 methyltransferase inhibitors.
• To explore allosteric inhibition of EZH2 by targeting the EED subunit.
• To develop a novel probe for efficient screening of EZH2 inhibitors.

Main Methods:

• Designed a fluorescence polarization (FP) probe based on known EED binding compounds.
• Utilized the FP probe to re-triage a previously generated HTS hit list.
• Identified novel allosteric inhibitors of PRC2 methyltransferase activity.

Main Results:

• The FP probe enabled rapid and clean re-evaluation of HTS hits.
• Successfully identified novel compounds that allosterically inhibit EZH2 activity.
• This approach circumvented issues associated with orthosteric EZH2 inhibition.

Conclusions:

• Allosteric inhibition of EZH2 via EED binding offers a promising therapeutic strategy, especially for resistant cancers.
• The developed FP probe is an effective tool for identifying allosteric PRC2 inhibitors.
• This study provides a foundation for developing new cancer therapies targeting the PRC2 complex.