4QR5

Brd4 Bromodomain 1 complex with its novel inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.41 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

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

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

(2015) J Med Chem 58: 1281-1297

  • DOI: https://doi.org/10.1021/jm501504k
  • Primary Citation of Related Structures:  
    4QR3, 4QR4, 4QR5

  • PubMed 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.


  • Organizational Affiliation

    Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, ‡Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, and §Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4125Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BNM
Query on BNM

Download Ideal Coordinates CCD File 
B [auth A]N-[3-(cyclopentylsulfamoyl)-5-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxamide
C18 H21 N3 O4 S2
OLJJIVPNEQZRJR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BNM Binding MOAD:  4QR5 IC50: 60 (nM) from 1 assay(s)
BindingDB:  4QR5 IC50: 60 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.41 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 31.74α = 90
b = 47.2β = 90
c = 79.27γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
Blu-Icedata collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-01
    Type: Initial release