6Q3Z

Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16k


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.

Watts, E.Heidenreich, D.Tucker, E.Raab, M.Strebhardt, K.Chesler, L.Knapp, S.Bellenie, B.Hoelder, S.

(2019) J Med Chem 62: 2618-2637

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01947
  • Primary Citation of Related Structures:  
    6Q3Y, 6Q3Z

  • PubMed Abstract: 

    Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.


  • Organizational Affiliation

    Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SM2 5NG , U.K.


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
HG8
Query on HG8

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-[(4-methylthiophen-2-yl)methyl]-7~{H}-pteridin-6-one
C29 H38 N6 O2 S
RKWOVOVDWBRGQO-XMMPIXPASA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
I [auth B]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
I [auth B],
J [auth B],
K [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HG8 Binding MOAD:  6Q3Z Kd: 44 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 30.151α = 84.38
b = 39.511β = 75.19
c = 55.721γ = 89.96
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-06
    Type: Initial release
  • Version 1.1: 2019-03-27
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description