PDBsum entry 5ctl

Signaling protein/inhibitor

PDB id: 5ctl

Contents

Protein chain

133 a.a.

Ligands

EB9

Waters ×10

PDB id:

5ctl

Name:

Signaling protein/inhibitor

Title:

Crystal structure of the first bromodomain of human brd4 in complex with benzo[cd]indol-2(1h)-one ligand

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: n-terminal bromodomain, unp residues 44-168. Synonym: protein hunk1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.51Å R-factor: 0.203 R-free: 0.227

Authors:

Y.Zhang,M.Song,Z.Liu,X.Xue,Y.Xu

Key ref:

X.Xue et al. (2016). Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation. J Med Chem, 59, 1565-1579. PubMed id: 26731490 DOI: 10.1021/acs.jmedchem.5b01511

Date:

24-Jul-15 Release date: 13-Jan-16

Protein chain

O60885  (BRD4_HUMAN) -  Bromodomain-containing protein 4 from Homo sapiens

Seq: 1362 a.a.

Struc: 133 a.a.*

* PDB and UniProt seqs differ at 11 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.5b01511

J Med Chem 59:1565-1579 (2016)

PubMed id: 26731490

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation.

X.Xue, Y.Zhang, Z.Liu, M.Song, Y.Xing, Q.Xiang, Z.Wang, Z.Tu, Y.Zhou, K.Ding, Y.Xu.

ABSTRACT

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.