4WIV

Crystal Structure of the first bromodomain of human BRD4 in complex with a novel inhibitor UMB32 (N-TERT-BUTYL-2-[4-(3,5-DIMETHYL-1,2-OXAZOL-4-YL) PHENYL]IMIDAZO[1,2-A]PYRAZIN-3-AMINE)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 

Starting Model: experimental
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This is version 1.4 of the entry. See complete history


Literature

Biased multicomponent reactions to develop novel bromodomain inhibitors.

McKeown, M.R.Shaw, D.L.Fu, H.Liu, S.Xu, X.Marineau, J.J.Huang, Y.Zhang, X.Buckley, D.L.Kadam, A.Zhang, Z.Blacklow, S.C.Qi, J.Zhang, W.Bradner, J.E.

(2014) J Med Chem 57: 9019-9027

  • DOI: https://doi.org/10.1021/jm501120z
  • Primary Citation of Related Structures:  
    4WIV

  • PubMed Abstract: 

    BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.


  • Organizational Affiliation

    Department of Medical Oncology, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.56 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.562α = 90
b = 49.21β = 90
c = 60.991γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-29
    Type: Initial release
  • Version 1.1: 2014-11-26
    Changes: Database references
  • Version 1.2: 2015-02-04
    Changes: Derived calculations
  • Version 1.3: 2015-08-26
    Changes: Other
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description