5Z5V

The first bromodomain of BRD4 with compound BDF-1253


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.66 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma.

Chen, W.Zhang, H.Chen, Z.Jiang, H.Liao, L.Fan, S.Xing, J.Xie, Y.Chen, S.Ding, H.Chen, K.Jiang, H.Luo, C.Zheng, M.Yao, Z.Huang, Y.Zhang, Y.

(2018) Oncogenesis 7: 83-83

  • DOI: https://doi.org/10.1038/s41389-018-0093-z
  • Primary Citation of Related Structures:  
    5Z5T, 5Z5U, 5Z5V

  • PubMed Abstract: 

    Small molecular inhibitors targeting BRD4 family proteins are emerging as promising therapies in many types of human malignancies. However, whether BRD4, as well as other BET family members, may serve as therapeutic targets in renal cell carcinoma (RCC) remains unknown. In this study, we found that both BRD2 and BRD4 were over-expressed in RCC tissues, knock-down both of which achieved potent anti-proliferative effects in RCC cells. A novel category of BET inhibitors, originated from an approved drug Nitroxoline, were synthesized and evaluated with biochemical and cellular assays, as well as the method of crystallography. The complex crystal structures of several compounds in this category with the first bromodomain of BRD4 (BRD4-BD1) were solved, revealing the binding mechanism and facilitating further structural optimizations. Among them, compound BDF-1253 showed an approximately four-fold improvement in BRD4 inhibition compared with the prototype Nitroxoline and had good selectivity for BET proteins against other bromodomain proteins or epi-enzymes in biochemical assays. Compound BDF-1253 efficiently suppressed the expression of BET downstream genes, impaired RCC cells viability via inducing cell cycle arrest and apoptosis, and decreased tumor growth in RCC xenografts. In summary, these results suggest that inhibition of BET family members has great therapeutic potentials in the treatment of RCC, and the novel series of BET inhibitors reported here are promising to become RCC drug candidates.


  • Organizational Affiliation

    Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4125Homo 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
96X
Query on 96X

Download Ideal Coordinates CCD File 
B [auth A]N-{8-hydroxy-4-[(1H-imidazol-1-yl)methyl]quinolin-2-yl}acetamide
C15 H14 N4 O2
IZQWAALUGBLUAZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
96X Binding MOAD:  5Z5V IC50: 287 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.66 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.037α = 90
b = 47.293β = 90
c = 79.081γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-01-23
    Type: Initial release
  • Version 1.1: 2019-03-06
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description