4YH3

Crystal structure of human BRD4(1) in complex with 4-[(2E)-3-(4-methoxyphenyl)-2-phenylprop-2-enoyl]-3,4-dihydroquinoxalin-2(1H)-one (compound 19a)

4YH3 の概要

• エントリーDOI: 10.2210/pdb4yh3/pdb
• 関連するPDBエントリー: 4YH4
• 分子名称: Bromodomain-containing protein 4, 4-[(2E)-3-(4-methoxyphenyl)-2-phenylprop-2-enoyl]-3,4-dihydroquinoxalin-2(1H)-one (3 entities in total)
• 機能のキーワード: brd4(1), protein binding
• 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: 15714.02

構造登録者

White, A.,Lakshminarasimhan, D.,Suto, R.K. (登録日: 2015-02-26, 公開日: 2016-01-13, 最終更新日: 2024-02-28)

主引用文献

Duffy, B.C.,Liu, S.,Martin, G.S.,Wang, R.,Hsia, M.M.,Zhao, H.,Guo, C.,Ellis, M.,Quinn, J.F.,Kharenko, O.A.,Norek, K.,Gesner, E.M.,Young, P.R.,McLure, K.G.,Wagner, G.S.,Lakshminarasimhan, D.,White, A.,Suto, R.K.,Hansen, H.C.,Kitchen, D.B.
Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.
Bioorg.Med.Chem.Lett., 25:2818-2823, 2015

PubMed Abstract: Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1).

PubMed: 26022843
DOI: 10.1016/j.bmcl.2015.04.107

実験手法

X-RAY DIFFRACTION (1.6 Å)