6AFR

Crystal Structure of the first bromodomain of human BRD4 in complex with 5-((4-fluoro-1H-imidazol-1-yl)methyl)quinolin-8-ol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors

Xing, J.Zhang, R.Jiang, X.Hu, T.Wang, X.Qiao, G.Wang, J.Yang, F.Luo, X.Chen, K.Shen, J.Luo, C.Jiang, H.Zheng, M.

(2018) Eur J Med Chem 163: 281-294

  • DOI: https://doi.org/10.1016/j.ejmech.2018.11.018
  • Primary Citation of Related Structures:  
    6AFR

  • PubMed Abstract: 

    Bromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment.


  • Organizational Affiliation

    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo 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
9E3 (Subject of Investigation/LOI)
Query on 9E3

Download Ideal Coordinates CCD File 
B [auth A]5-[(4-fluoranylimidazol-1-yl)methyl]quinolin-8-ol
C13 H10 F N3 O
XHVDVFNHQJLOBV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
9E3 Binding MOAD:  6AFR IC50: 70 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 31.98α = 90
b = 47.208β = 90
c = 78.737γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Chinese Academy of SciencesChinaXDA12050201

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-12
    Type: Initial release
  • Version 1.1: 2018-12-26
    Changes: Data collection, Database references