Biological Activity:

EED226 is a potent and selective allosteric PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. In the in vitro enzymatic assays, EED226 inhibits PRC2 with an IC₅₀ of 23.4 nM when the H3K27me0 peptide is used as substrate and an IC₅₀ of 53.5 nM when the mononucleosome is used as the substrate. It is noncompetitive with both SAM and peptide substrate. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors, and shows a synergistic effect to inhibit cancer cell growth when combined with EZH2 inhibitors. Such results indicate that targeting the H3K27me3 pocket in EED is a promising approach for treating cancers that are dependent on PRC2 activity.


How to Use:

In vitro: EED226 was used at 10 µM in vitro and cellular assays.
In vivo: EED226 was dosed orally to mice at 4-80 mg/kg twice a day (BID dosing) in subcutaneous Karpas422 xenograft tumor model.

Reference:

• 1. Qi W, et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. (2017) Nat Chem Biol. 13(4):381-388. 
• 2. Huang Y, et al. Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. (2017) J Med Chem. 60(6):2215-2226. 
• 3. Li L, et al. Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED. (2017) PLoS One. 12(1):e0169855.