5UOO

BRD4 bromodomain 2 in complex with CD161


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor.

Zhao, Y.Bai, L.Liu, L.McEachern, D.Stuckey, J.A.Meagher, J.L.Yang, C.Y.Ran, X.Zhou, B.Hu, Y.Li, X.Wen, B.Zhao, T.Li, S.Sun, D.Wang, S.

(2017) J Med Chem 60: 3887-3901

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00193
  • Primary Citation of Related Structures:  
    5UOO

  • PubMed Abstract: 

    We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.


  • Organizational Affiliation

    Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4131Homo 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
8FV
Query on 8FV

Download Ideal Coordinates CCD File 
B [auth A]7-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indole
C26 H21 N5 O2
AEANZCXROGPSBY-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
8FV BindingDB:  5UOO Ki: min: 1.4, max: 8.2 (nM) from 2 assay(s)
Kd: min: 1.8, max: 8.4 (nM) from 3 assay(s)
IC50: min: 7.2, max: 28 (nM) from 2 assay(s)
Binding MOAD:  5UOO Ki: 1.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.69 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.188α = 90
b = 72.793β = 90
c = 32.117γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data scaling
PHASERphasing
PDB_EXTRACTdata extraction
HKL-2000data reduction
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-17
    Type: Initial release
  • Version 1.1: 2017-05-24
    Changes: Data collection, Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description