7P3C

EED in complex with compound 4

7P3C の概要

• エントリーDOI: 10.2210/pdb7p3c/pdb
• 分子名称: Polycomb protein EED, N-(2,3-dihydro-1-benzofuran-4-ylmethyl)-8-(4-methylsulfonylphenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine, N-[5-[(5-fluoranyl-2,3-dihydro-1-benzofuran-4-yl)methylamino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl]benzamide, ... (4 entities in total)
• 機能のキーワード: methyl transferase eed prc2 epigenetic h3k27 wd40 inhibitor, protein binding
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85424.26

構造登録者

Read, J.A. (登録日: 2021-07-07, 公開日: 2021-12-08, 最終更新日: 2024-01-31)

主引用文献

Bagal, S.K.,Gregson, C.,O' Donovan, D.H.,Pike, K.G.,Bloecher, A.,Barton, P.,Borodovsky, A.,Code, E.,Fillery, S.M.,Hsu, J.H.,Kawatkar, S.P.,Li, C.,Longmire, D.,Nai, Y.,Nash, S.C.,Pike, A.,Robinson, J.,Read, J.A.,Rawlins, P.B.,Shen, M.,Tang, J.,Wang, P.,Woods, H.,Williamson, B.
Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.
J.Med.Chem., 64:17146-17183, 2021

PubMed 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.

PubMed: 34807608
DOI: 10.1021/acs.jmedchem.1c01161

実験手法

X-RAY DIFFRACTION (1.61 Å)