Journal of medicinal chemistry · 2021
Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.
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Bagal Sharan K, Gregson Clare, O' Donovan Daniel H, Pike Kurt G, Bloecher Andrew, Barton Peter, Borodovsky Alexandra, Code Erin, Fillery Shaun M, Hsu Jessie Hao-Ru, Kawatkar Sameer P, Li Chengzhi, Longmire David, Nai Youfeng, Nash Samuel C, Pike Andrew, Robinson James, Read Jon A, Rawlins Phillip B, Shen Minhui, Tang Jia, Wang Peng, Woods Haley, Williamson Beth
Аннотация
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.