5A85

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 8-(3R,4R)-3-(cyclohexylmethoxy)piperidin-4-ylamino-3-methyl-1,2-dihydro-1,7- naphthyridin-2-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.188 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Optimization of Naphthyridones Into Potent Atad2 Bromodomain Inhibitors.

Bamborough, P.Chung, C.Furze, R.C.Grandi, P.Michon, A.Sheppard, R.J.Barnett, H.Diallo, H.Dixon, D.P.Douault, C.Jones, E.J.Karamshi, B.Mitchell, D.J.Prinjha, R.K.Rau, C.Watson, R.J.Werner, T.Demont, E.H.

(2015) J Med Chem 58: 6151

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00773
  • Primary Citation of Related Structures:  
    5A81, 5A82, 5A83, 5A85

  • PubMed Abstract: 

    ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.


  • Organizational Affiliation

    ∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 4127Homo sapiensMutation(s): 0 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
78J
Query on 78J

Download Ideal Coordinates CCD File 
C [auth A](3R,4R)-3-(cyclohexylmethoxy)piperidin-4-yl]amino}-3-methyl-1,2-dihydro-1,7-naphthyridin-2-one
C21 H30 N4 O2
DQJOFVKRLCBKNO-QZTJIDSGSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
78J Binding MOAD:  5A85 IC50: 5010 (nM) from 1 assay(s)
BindingDB:  5A85 IC50: min: 3981, max: 5012 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.189α = 90
b = 48.652β = 90
c = 61.052γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2015-08-26
    Changes: Database references