4HXM

Brd4 Bromodomain 1 complex with N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}BUTANAMIDE inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.

Zhao, L.Cao, D.Chen, T.Wang, Y.Miao, Z.Xu, Y.Chen, W.Wang, X.Li, Y.Du, Z.Xiong, B.Li, J.Xu, C.Zhang, N.He, J.Shen, J.

(2013) J Med Chem 56: 3833-3851

  • DOI: https://doi.org/10.1021/jm301793a
  • Primary Citation of Related Structures:  
    4HXK, 4HXL, 4HXM, 4HXN, 4HXO, 4HXP, 4HXR, 4HXS

  • PubMed Abstract: 

    Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.


  • Organizational Affiliation

    Department of Medicinal Chemistry, State Key Laboratory of Drug Research, 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 4124Homo 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
1A8
Query on 1A8

Download Ideal Coordinates CCD File 
B [auth A]N-{3-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)-5-[(thiophen-2-ylsulfonyl)amino]phenyl}butanamide
C17 H17 N3 O4 S3
KWWYOIOTRAVAHK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1A8 BindingDB:  4HXM IC50: 790 (nM) from 1 assay(s)
PDBBind:  4HXM IC50: 790 (nM) from 1 assay(s)
Binding MOAD:  4HXM IC50: 790 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.07α = 90
b = 47.13β = 90
c = 79.23γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
Blu-Icedata collection
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-03
    Type: Initial release
  • Version 1.1: 2013-04-10
    Changes: Structure summary
  • Version 1.2: 2013-06-19
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations