5D26

First bromodomain of BRD4 bound to inhibitor XD28

Summary for 5D26

• Entry DOI: 10.2210/pdb5d26/pdb
• Descriptor: Bromodomain-containing protein 4, N~2~-[5-(diethylsulfamoyl)-2-hydroxyphenyl]-3-ethyl-5-methyl-1H-pyrrole-2,4-dicarboxamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: gene regulation, bromodomain, inhibitor, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15697.06

Authors

Wohlwend, D.,Huegle, M. (deposition date: 2015-08-05, release date: 2016-01-20, Last modification date: 2024-05-08)

Primary citation

Hugle, M.,Lucas, X.,Weitzel, G.,Ostrovskyi, D.,Breit, B.,Gerhardt, S.,Einsle, O.,Gunther, S.,Wohlwend, D.
4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1).
J.Med.Chem., 59:1518-1530, 2016

PubMed Abstract: Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013, 52, 14055]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4-related malignancies.

PubMed: 26731611
DOI: 10.1021/acs.jmedchem.5b01267

Experimental method

X-RAY DIFFRACTION (1.82 Å)