4BW1

The first bromodomain of human BRD4 in complex with 3,5 dimethylisoxaxole ligand

4BW1 の概要

• エントリーDOI: 10.2210/pdb4bw1/pdb
• 関連するPDBエントリー: 4BW2 4BW3 4BW4
• 分子名称: BROMODOMAIN-CONTAINING PROTEIN 4, 1,2-ETHANEDIOL, 4-[(2-tert-butylphenyl)amino]-7-(3,5-dimethyl-1,2-oxazol-4-yl)quinoline-3-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: transcription, inhibitor, histone, epigenetic reader, antagonist
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15701.07

構造登録者

Chung, C.,Mirguet, O.,Lamotte, Y.,Bamborough, P.,Delannee, D.,Bouillot, A.,Gellibert, F.,Krysa, G.,Lewis, A.,Witherington, J.,Huet, P.,Dudit, Y.,Trottet, L.,Nicodeme, E. (登録日: 2013-06-29, 公開日: 2013-09-11, 最終更新日: 2024-05-08)

主引用文献

Mirguet, O.,Lamotte, Y.,Chung, C.,Bamborough, P.,Delannee, D.,Bouillot, A.,Gellibert, F.,Krysa, G.,Lewis, A.,Witherington, J.,Huet, P.,Dudit, Y.,Trottet, L.,Nicodeme, E.
Naphthyridines as Novel Bet Family Bromodomain Inhibitors.
Chemmedchem, 9:589-, 2014

PubMed Abstract: Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.

PubMed: 24000170
DOI: 10.1002/CMDC.201300259

実験手法

X-RAY DIFFRACTION (1.4 Å)