4Z1Q

Crystal structure of the first bromodomain of human BRD4 bound to benzotriazolo-diazepine scaffold


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

Taylor, A.M.Vaswani, R.G.Gehling, V.S.Hewitt, M.C.Leblanc, Y.Audia, J.E.Bellon, S.Cummings, R.T.Cote, A.Harmange, J.C.Jayaram, H.Joshi, S.Lora, J.M.Mertz, J.A.Neiss, A.Pardo, E.Nasveschuk, C.G.Poy, F.Sandy, P.Setser, J.W.Sims, R.J.Tang, Y.Albrecht, B.K.

(2016) ACS Med Chem Lett 7: 145-150

  • DOI: https://doi.org/10.1021/ml500411h
  • Primary Citation of Related Structures:  
    4X2I, 4Z1Q, 4Z1S

  • PubMed Abstract: 

    Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.


  • 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 4
A, B
127Homo 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
558
Query on 558

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-[(4R)-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-8-yl]pyridin-2-amine
C23 H21 Cl N6
SBRJLPKKZHHGCO-CQSZACIVSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
558 Binding MOAD:  4Z1Q IC50: 15 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 30.293α = 83.07
b = 39.501β = 75.35
c = 57.23γ = 89.85
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
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: 2015-04-08
    Type: Initial release
  • Version 1.1: 2016-03-30
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations