6C7Q

BRD4 BD2 in complex with compound CE277


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.51 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor.

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

(2018) J Med Chem 61: 6110-6120

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00483
  • Primary Citation of Related Structures:  
    6C7Q, 6C7R

  • PubMed Abstract: 

    We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K i values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.


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
EO1
Query on EO1

Download Ideal Coordinates CCD File 
B [auth A]7-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-2-methyl-N-(1-methyl-1H-indazol-3-yl)-9H-pyrimido[4,5-b]indol-4-amine
C25 H23 N7 O2
MQUZTKXBCFOZRW-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
EO1 BindingDB:  6C7Q Ki: 0.7 (nM) from 1 assay(s)
IC50: 9.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.51 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.193 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.176α = 90
b = 72.647β = 90
c = 32.222γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-01
    Type: Initial release
  • Version 1.1: 2018-08-08
    Changes: Data collection, Database references