Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase
Sharan K. Bagal, Clare Gregson, Daniel H. O’Donovan, Kurt G. Pike, Andrew Bloecher, Peter Barton, Alexandra Borodovsky, Erin Code, Shaun Fillery, Jessie Hao-Ru Hsu, Sameer Kawatkar, Chengzhi Li, David Longmire, Youfeng Nai, Samuel Nash, Andrew Pike, James Robinson, Jon Read, Phillip B. Rawlins, Minhui Shen, Jia Tang, Peng Wang, Haley Woods, Beth Williamson
Abstract
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.