5CP5: Crystal Structure Of The First Bromodomain Of Human Brd4 In Complex With Benzo[cd]indol-2(1h)-one Ligand

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.
PDB ID: 5CP5Download
MMDB ID: 135449
PDB Deposition Date: 2015/7/21
Updated in MMDB: 2016/03
Experimental Method:
x-ray diffraction
Resolution: 1.79  Å
Source Organism:
Similar Structures:
Biological Unit for 5CP5: monomeric; determined by author
Molecular Components in 5CP5
Label Count Molecule
Protein (1 molecule)
Bromodomain-containing Protein 4(Gene symbol: BRD4)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB