Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.
Basic Information
ID: ALA4831554
Journal: J Med Chem
Title: Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.
Authors: Bagal SK, Gregson C, O' Donovan DH, Pike KG, Bloecher A, Barton P, Borodovsky A, Code E, Fillery SM, Hsu JH, Kawatkar SP, Li C, Longmire D, Nai Y, Nash SC, Pike A, Robinson J, Read JA, Rawlins PB, Shen M, Tang J, Wang P, Woods H, Williamson B.
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.
CiteXplore: 34807608
DOI: 10.1021/acs.jmedchem.1c01161
Patent ID: ┄