4X2I

Discovery of benzotriazolo diazepines as orally-active inhibitors of BET bromodomains: Crystal structure of BRD4 with CPI-13


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.138 
  • R-Value Observed: 0.141 

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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 4126Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3X0
Query on 3X0

Download Ideal Coordinates CCD File 
C [auth A](4R)-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine
C18 H17 Cl N4
DGXRMQACSNETBM-GFCCVEGCSA-N
FMT
Query on FMT

Download Ideal Coordinates CCD File 
B [auth A]FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3X0 Binding MOAD:  4X2I IC50: 350 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.138 
  • R-Value Observed: 0.141 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.905α = 90
b = 48.181β = 90
c = 78.314γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-11
    Type: Initial release
  • Version 1.1: 2016-03-30
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations