Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy

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).
Herein we disclose the discovery of a first-in-class potent, selective,
and orally bioavailable EED inhibitor compound 43 (EED226).
Guided by X-ray crystallography, compound 43 was discovered
by fragmentation and regrowth of compound 7, a PRC2 HTS
hit that directly binds EED. The ensuing scaffold hopping followed
by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression
in EZH2MUT preclinical DLBCL model. For the first time
we demonstrate that specific and direct inhibition of EED can be effective
as an anticancer strategy.