EED226

Description: EED226 is a first-in-class potent, potent, selective, orally bioavailable and allosteric inhibitor of embryonic ectoderm development (EED) with potential anticancer activity. It has an IC50 of 22 nM when the H3K27me0 peptide was used as substrate and an IC50 of 53.5 nM when the mononucleosome was used as the substrate. Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). EED226 directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity.

References: Nat Chem Biol. 2017 Apr; 13(4):381-388; Cancer Discov. 2017 Apr; 7(4):OF8.