Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

PRC2
is a multisubunit methyltransferase involved in epigenetic
regulation of early embryonic development and cell growth. The catalytic
subunit EZH2 methylates primarily lysine 27 of histone H3, leading
to chromatin compaction and repression of tumor suppressor genes.
Inhibiting this activity by small molecules targeting EZH2 was shown
to result in antitumor efficacy. Here, we describe the optimization
of a chemical series representing a new class of PRC2 inhibitors which
acts allosterically via the trimethyllysine pocket of the noncatalytic
EED subunit. Deconstruction of a larger and complex screening hit
to a simple fragment-sized molecule followed by structure-guided regrowth
and careful property modulation were employed to yield compounds which
achieve submicromolar inhibition in functional assays and cellular
activity. The resulting molecules can serve as a simplified entry
point for lead optimization and can be utilized to study this new
mechanism of PRC2 inhibition and the associated biology in detail.