5YOV

Crystal structure of BRD4-BD1 bound with hjp126


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.189 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups.

Hu, J.Wang, Y.Li, Y.Cao, D.Xu, L.Song, S.Damaneh, M.S.Li, J.Chen, Y.Wang, X.Chen, L.Shen, J.Miao, Z.Xiong, B.

(2018) Eur J Med Chem 150: 156-175

  • DOI: https://doi.org/10.1016/j.ejmech.2018.02.070
  • Primary Citation of Related Structures:  
    5YOV

  • PubMed Abstract: 

    Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9, 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 μM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors.


  • Organizational Affiliation

    Department of Medicinal Chemistry, 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, NO.19A 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): 1 
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
8XR
Query on 8XR

Download Ideal Coordinates CCD File 
B [auth A](3~{R})-4-cyclopentyl-~{N}-(2,4-dimethylphenyl)-1,3-dimethyl-2-oxidanylidene-3~{H}-quinoxaline-6-carboxamide
C24 H29 N3 O2
DOTVVPFDFURPQD-QGZVFWFLSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8XR BindingDB:  5YOV IC50: 21 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.34α = 90
b = 47.435β = 90
c = 78.926γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata scaling
PHENIXmodel building
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: 2018-11-07
    Type: Initial release
  • Version 1.1: 2019-11-20
    Changes: Database references, Structure summary