5UEU

BRD4_BD2_A-1107604


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Wang, L.Pratt, J.K.Soltwedel, T.Sheppard, G.S.Fidanze, S.D.Liu, D.Hasvold, L.A.Mantei, R.A.Holms, J.H.McClellan, W.J.Wendt, M.D.Wada, C.Frey, R.Hansen, T.M.Hubbard, R.Park, C.H.Li, L.Magoc, T.J.Albert, D.H.Lin, X.Warder, S.E.Kovar, P.Huang, X.Wilcox, D.Wang, R.Rajaraman, G.Petros, A.M.Hutchins, C.W.Panchal, S.C.Sun, C.Elmore, S.W.Shen, Y.Kati, W.M.McDaniel, K.F.

(2017) J Med Chem 60: 3828-3850

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00017
  • Primary Citation of Related Structures:  
    5UEU, 5UEW, 5UEX, 5UEY, 5UEZ, 5UF0

  • PubMed Abstract: 

    Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K i = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.


  • Organizational Affiliation

    AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4
A, B
109Homo 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
0S6
Query on 0S6

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
methyl [(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate
C20 H19 Cl N4 O2 S
GGRCIHACOIMRKY-HNNXBMFYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0S6 BindingDB:  5UEU Ki: 17 (nM) from 1 assay(s)
IC50: 18.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.826α = 90
b = 64.544β = 90
c = 75.287γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
SCALAdata scaling
Cootmodel building
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-05-10 
  • Deposition Author(s): Park, C.H.

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-10
    Type: Initial release
  • Version 1.1: 2017-05-24
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references