4UYF

N-Terminal bromodomain of Human BRD2 with I-BET726 (GSK1324726A)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The Discovery of I-Bet726 (Gsk1324726A), a Potent Tetrahydroquinoline Apoa1 Up-Regulator and Selective Bet Bromodomain Inhibitor.

Gosmini, R.Nguyen, V.L.Toum, J.Simon, C.Brusq, J.M.Krysa, G.Mirguet, O.Riou-Eymard, A.M.Boursier, E.V.Trottet, L.Bamborough, P.Clark, H.Chung, C.W.Cutler, L.Demont, E.H.Kaur, R.Lewis, A.J.Schilling, M.B.Soden, P.E.Taylor, S.Walker, A.L.Walker, M.D.Prinjha, R.K.Nicodeme, E.

(2014) J Med Chem 57: 8111

  • DOI: https://doi.org/10.1021/jm5010539
  • Primary Citation of Related Structures:  
    4UYF, 4UYG, 4UYH

  • PubMed Abstract: 

    Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.


  • Organizational Affiliation

    Candidate Discovery, ‡Discovery Biology, §DMPK, GlaxoSmithKline Les Ulis, Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 Avenue du Québec, 91140 Villebon-sur-Yvette, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 2154Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens)
Explore P25440 
Go to UniProtKB:  P25440
PHAROS:  P25440
GTEx:  ENSG00000204256 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25440
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 2
B, C
154Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens)
Explore P25440 
Go to UniProtKB:  P25440
PHAROS:  P25440
GTEx:  ENSG00000204256 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25440
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
73B
Query on 73B

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C]
4-[(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]benzoic acid
C25 H23 Cl N2 O3
FAWSUKOIROHXAP-NPMXOYFQSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B],
J [auth C]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
73B Binding MOAD:  4UYF Kd: 4.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.064α = 90
b = 55.597β = 93.99
c = 67.266γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-08
    Type: Initial release
  • Version 1.1: 2014-10-22
    Changes: Database references
  • Version 1.2: 2019-05-15
    Changes: Data collection, Experimental preparation, Other