4QR4: Brd4 Bromodomain 1 Complex With Its Novel Inhibitors

The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 muM in FP binding assay and GI50 of 0.1-0.3 muM in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.
PDB ID: 4QR4Download
MMDB ID: 130457
PDB Deposition Date: 2014/6/30
Updated in MMDB: 2015/07
Experimental Method:
x-ray diffraction
Resolution: 1.28  Å
Source Organism:
Similar Structures:
Biological Unit for 4QR4: monomeric; determined by author and by software (PISA)
Molecular Components in 4QR4
Label Count Molecule
Protein (1 molecule)
Bromodomain-containing Protein 4(Gene symbol: BRD4)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB