4OGI

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor BI-2536


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.

Ciceri, P.Muller, S.O'Mahony, A.Fedorov, O.Filippakopoulos, P.Hunt, J.P.Lasater, E.A.Pallares, G.Picaud, S.Wells, C.Martin, S.Wodicka, L.M.Shah, N.P.Treiber, D.K.Knapp, S.

(2014) Nat Chem Biol 10: 305-312

  • DOI: https://doi.org/10.1038/nchembio.1471
  • Primary Citation of Related Structures:  
    4OGI, 4OGJ

  • PubMed Abstract: 

    Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.


  • Organizational Affiliation

    1] KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA. [2].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4
A, B
127Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
R78
Query on R78

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
C28 H39 N7 O3
XQVVPGYIWAGRNI-JOCHJYFZSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
R78 BindingDB:  4OGI Ki: 56 (nM) from 1 assay(s)
Kd: min: 24, max: 87 (nM) from 3 assay(s)
IC50: min: 1.2, max: 300 (nM) from 8 assay(s)
Binding MOAD:  4OGI Kd: 37 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.243α = 90
b = 59.64β = 90
c = 115.345γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-26
    Type: Initial release
  • Version 1.1: 2014-04-02
    Changes: Database references
  • Version 1.2: 2018-01-31
    Changes: Structure summary
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description