6MH1

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH HU-10, A 1,4,5-Trisubstituted Imidazole Analogue

Summary for 6MH1

• Entry DOI: 10.2210/pdb6mh1/pdb
• Descriptor: Bromodomain-containing protein 4, N-(3,5-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: cap, hunk1, mcap, protein binding-inhibitor complex, inhibitor, transcription-inhibitor complex, inflammation, map-kinase inhibition, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 31270.03

Authors

Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2018-09-17, release date: 2019-08-07, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)