EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex

Area of Science:

• Epigenetics
• Cancer Biology
• Drug Discovery

Background:

• Polycomb Repressive Complex 2 (PRC2) deregulation, involving EZH2, SUZ12, and EED, leads to H3K27 hypermethylation and promotes cancer.
• While EZH2 inhibitors show clinical promise, acquired resistance through EZH2 mutations limits their efficacy.

Purpose of the Study:

• To develop novel hetero-bifunctional proteolysis-targeting chimeras (PROTACs) to eliminate the EED subunit of PRC2.
• To overcome resistance mechanisms associated with EZH2 inhibitors.

Main Methods:

• Design and synthesis of novel PROTACs targeting EED.
• Biochemical assays to assess PROTAC binding affinity (pK_D) and enzyme inhibition (pIC₅₀).
• Cell-based assays to evaluate PRC2 subunit degradation and cancer cell proliferation inhibition (GI₅₀).

Main Results:

• PROTACs demonstrated high affinity for EED (pK_D ∼ 9.0) and potent inhibition of PRC2 activity (pIC₅₀ ∼ 8.1).
• PROTACs induced rapid degradation of EED, EZH2, and SUZ12.
• Selective inhibition of proliferation in PRC2-dependent cancer cells was observed (GI₅₀ = 49-58 nM).

Conclusions:

• PROTACs targeting EED offer a viable strategy for degrading PRC2 complex components.
• This PROTAC-mediated degradation mechanism presents a therapeutic modality for PRC2-dependent cancers, potentially overcoming resistance to EZH2 inhibitors.