5HLS

Crystal structure of the first bromodomain of human BRD4 bound to CPI-0610


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.

Albrecht, B.K.Gehling, V.S.Hewitt, M.C.Vaswani, R.G.Cote, A.Leblanc, Y.Nasveschuk, C.G.Bellon, S.Bergeron, L.Campbell, R.Cantone, N.Cooper, M.R.Cummings, R.T.Jayaram, H.Joshi, S.Mertz, J.A.Neiss, A.Normant, E.O'Meara, M.Pardo, E.Poy, F.Sandy, P.Supko, J.Sims, R.J.Harmange, J.C.Taylor, A.M.Audia, J.E.

(2016) J Med Chem 59: 1330-1339

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01882
  • Primary Citation of Related Structures:  
    5HLS, 5HM0

  • PubMed Abstract: 

    In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).


  • Organizational Affiliation

    Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4128Homo 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
62G
Query on 62G

Download Ideal Coordinates CCD File 
B [auth A]CPI-0610
C20 H16 Cl N3 O2
GCWIQUVXWZWCLE-INIZCTEOSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
62G Binding MOAD:  5HLS IC50: 39 (nM) from 1 assay(s)
BindingDB:  5HLS IC50: min: 18, max: 39 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.788α = 90
b = 47.634β = 90
c = 77.775γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata 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: 2016-02-10
    Type: Initial release
  • Version 1.1: 2016-03-09
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description