7OE9

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH rac-N5-((1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl)-N7,3-dimethyl-3-phenyl-2,3-dihydrobenzofuran-5,7-dicarboxamide

7OE9 の概要

• エントリーDOI: 10.2210/pdb7oe9/pdb
• 関連するPDBエントリー: 7OE8
• 分子名称: Bromodomain-containing protein 2, (3S)-N7,3-dimethyl-N5-[(1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl]-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: inhibitor, bromodomain, nuclear protein
• 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: 13949.05

構造登録者

Chung, C. (登録日: 2021-05-02, 公開日: 2021-07-28, 最終更新日: 2024-05-01)

主引用文献

Lucas, S.C.C.,Atkinson, S.J.,Chung, C.W.,Davis, R.,Gordon, L.,Grandi, P.,Gray, J.J.R.,Grimes, T.,Phillipou, A.,Preston, A.G.,Prinjha, R.K.,Rioja, I.,Taylor, S.,Tomkinson, N.C.O.,Wall, I.,Watson, R.J.,Woolven, J.,Demont, E.H.
Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors.
J.Med.Chem., 64:10711-10741, 2021

PubMed Abstract: Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor (GSK852): a potent, 1000-fold-selective, highly soluble compound with good rat and dog pharmacokinetics.

PubMed: 34260229
DOI: 10.1021/acs.jmedchem.1c00344

実験手法

X-RAY DIFFRACTION (1.602 Å)