Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase

Aberrant activity of the histone
methyltransferase polycomb repressive
complex 2 (PRC2) has been linked to several cancers, with small-molecule
inhibitors of the catalytic subunit of the PRC2 enhancer of zeste
homologue 2 (EZH2) being recently approved for the treatment of epithelioid
sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the
EED subunit of PRC2 have recently emerged as allosteric inhibitors
of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors
that target EZH2, small molecules that bind to EED retain their efficacy
in EZH2 inhibitor-resistant cell lines. In this paper we disclose
the discovery of potent and orally bioavailable EED ligands with good
solubilities. The solubility of the EED ligands was optimized through
a variety of design tactics, with the resulting compounds exhibiting
in vivo efficacy in EZH2-driven tumors.