5KU3

BRD4 bromodomain in complex with Cpd59 ((S)-1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.14 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.165 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.

Crawford, T.D.Romero, F.A.Lai, K.W.Tsui, V.Taylor, A.M.de Leon Boenig, G.Noland, C.L.Murray, J.Ly, J.Choo, E.F.Hunsaker, T.L.Chan, E.W.Merchant, M.Kharbanda, S.Gascoigne, K.E.Kaufman, S.Beresini, M.H.Liao, J.Liu, W.Chen, K.X.Chen, Z.Conery, A.R.Cote, A.Jayaram, H.Jiang, Y.Kiefer, J.R.Kleinheinz, T.Li, Y.Maher, J.Pardo, E.Poy, F.Spillane, K.L.Wang, F.Wang, J.Wei, X.Xu, Z.Xu, Z.Yen, I.Zawadzke, L.Zhu, X.Bellon, S.Cummings, R.Cochran, A.G.Albrecht, B.K.Magnuson, S.

(2016) J Med Chem 59: 10549-10563

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01022
  • Primary Citation of Related Structures:  
    5KTU, 5KTW, 5KTX, 5KU3

  • PubMed Abstract: 

    The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC 50 = 0.02 μM, BRET IC 50 = 0.41 μM, BRD4(1) IC 50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.


  • Organizational Affiliation

    Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4126Homo 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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6XH
Query on 6XH

Download Ideal Coordinates CCD File 
L [auth A]1-[3-[[2-fluoranyl-4-(1-methylpyrazol-4-yl)phenyl]amino]-1-[(3~{S})-oxolan-3-yl]-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridin-5-yl]ethanone
C22 H25 F N6 O2
NKOJNOBJGYTLLZ-KRWDZBQOSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
K [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6XH BindingDB:  5KU3 IC50: min: 5490, max: 1.30e+4 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.14 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.165 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.037α = 90
b = 53.115β = 90
c = 106.745γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-02
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references