6W7F

Structure of EED bound to inhibitor 5285

6W7F の概要

• エントリーDOI: 10.2210/pdb6w7f/pdb
• 分子名称: Polycomb protein EED, 8-(6-cyclopropylpyridin-3-yl)-N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: inhibitor, gene regulation, transcription-inhibitor complex
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43463.33

構造登録者

Petrunak, E.M.,Stuckey, J.A. (登録日: 2020-03-19, 公開日: 2020-07-08, 最終更新日: 2023-10-18)

主引用文献

Rej, R.K.,Wang, C.,Lu, J.,Wang, M.,Petrunak, E.,Zawacki, K.P.,McEachern, D.,Fernandez-Salas, E.,Yang, C.Y.,Wang, L.,Li, R.,Chinnaswamy, K.,Wen, B.,Sun, D.,Stuckey, J.,Zhou, Y.,Chen, J.,Tang, G.,Wang, S.
EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development.
J.Med.Chem., 63:7252-7267, 2020

PubMed Abstract: Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC value of 0.2 nM and inhibits cell growth with IC values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date.

PubMed: 32580550
DOI: 10.1021/acs.jmedchem.0c00479

実験手法

X-RAY DIFFRACTION (2.2 Å)