6C7R

BRD4 BD1 in complex with compound CF53


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.210 

wwPDB Validation   3D Report Full Report


This is version 1.2 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 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
EO4
Query on EO4

Download Ideal Coordinates CCD File 
B [auth A]N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-2-methyl-9H-pyrimido[4,5-b]indol-4-amine
C24 H25 N7 O2
JIYPVUCBRQNICX-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EO4 BindingDB:  6C7R Ki: 1 (nM) from 1 assay(s)
Kd: min: 0.8, max: 2.2 (nM) from 2 assay(s)
IC50: 2 (nM) from 1 assay(s)
Binding MOAD:  6C7R Kd: 2.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.210 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 30.377α = 90
b = 41.471β = 94.87
c = 47.981γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
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
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description