5D26: First Bromodomain Of Brd4 Bound To Inhibitor Xd28

Citation:
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.
PDB ID: 5D26Download
MMDB ID: 135733
PDB Deposition Date: 2015/8/5
Updated in MMDB: 2017/09
Experimental Method:
x-ray diffraction
Resolution: 1.82  Å
Source Organism:
Similar Structures:
Biological Unit for 5D26: monomeric; determined by author and by software (PISA)
Molecular Components in 5D26
Label Count Molecule
Protein (1 molecule)
1
Bromodomain-containing Protein 4(Gene symbol: BRD4)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

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