4J0R

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand

4J0R の概要

• エントリーDOI: 10.2210/pdb4j0r/pdb
• 関連するPDBエントリー: 4J0S
• 分子名称: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[(R)-hydroxy(phenyl)methyl]phenol, ... (5 entities in total)
• 機能のキーワード: brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein, isoxazole, structural genomics consortium, sgc, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15769.89

構造登録者

Filippakopoulos, P.,Picaud, S.,Qi, J.,Felletar, I.,Hewings, D.S.,von Delft, F.,Conway, S.J.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2013-01-31, 公開日: 2013-02-13, 最終更新日: 2023-09-20)

主引用文献

Hewings, D.S.,Fedorov, O.,Filippakopoulos, P.,Martin, S.,Picaud, S.,Tumber, A.,Wells, C.,Olcina, M.M.,Freeman, K.,Gill, A.,Ritchie, A.J.,Sheppard, D.W.,Russell, A.J.,Hammond, E.M.,Knapp, S.,Brennan, P.E.,Conway, S.J.
Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.
J.Med.Chem., 56:3217-3227, 2013

PubMed Abstract: The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

PubMed: 23517011
DOI: 10.1021/jm301588r

実験手法

X-RAY DIFFRACTION (1.72 Å)