6MH7

Crystal structure of the first bromodomain of human BRD4 in complex with SKT-68, a 1,4,5-trisubstituted imidazole analogue

6MH7 の概要

• エントリーDOI: 10.2210/pdb6mh7/pdb
• 分子名称: Bromodomain-containing protein 4, N-(3,4-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, inhibitor, transcription-inhibitor complex, inflammation, 19f-nmr, map-kinase inhibition, protein binding/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31410.23

構造登録者

Zhu, J.-Y.,Schonbrunn, E. (登録日: 2018-09-17, 公開日: 2019-08-07, 最終更新日: 2023-10-11)

主引用文献

Divakaran, A.,Talluri, S.K.,Ayoub, A.M.,Mishra, N.K.,Cui, H.,Widen, J.C.,Berndt, N.,Zhu, J.Y.,Carlson, A.S.,Topczewski, J.J.,Schonbrunn, E.K.,Harki, D.A.,Pomerantz, W.C.K.
Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.
J.Med.Chem., 61:9316-9334, 2018

PubMed Abstract: As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.

PubMed: 30253095
DOI: 10.1021/acs.jmedchem.8b01248

実験手法

X-RAY DIFFRACTION (1.74 Å)