PDBsum entry 4qr4

Transcription/transcription inhibitor

PDB id: 4qr4

Contents

Protein chain

125 a.a.

Ligands

BNK

Waters ×160

PDB id:

4qr4

Name:

Transcription/transcription inhibitor

Title:

Brd4 bromodomain 1 complex with its novel inhibitors

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: unp residues 44-166. 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:

1.28Å R-factor: 0.163 R-free: 0.177

Authors:

B.Xiong,D.Y.Cao,T.T.Chen,Y.C.Xu

Key ref:

L.Zhao et al. (2015). Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization. J Med Chem, 58, 1281-1297. PubMed id: 25559428 DOI: 10.1021/jm501504k

Date:

30-Jun-14 Release date: 01-Jul-15

Protein chain

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

Seq: 1362 a.a.

Struc: 125 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/jm501504k

J Med Chem 58:1281-1297 (2015)

PubMed id: 25559428

Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization.

L.Zhao, Y.Wang, D.Cao, T.Chen, Q.Wang, Y.Li, Y.Xu, N.Zhang, X.Wang, D.Chen, L.Chen, Y.L.Chen, G.Xia, Z.Shi, Y.C.Liu, Y.Lin, Z.Miao, J.Shen, B.Xiong.

ABSTRACT

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 μM in FP binding assay and GI50 of 0.1-0.3 μM 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.