5U2E

BRD4 first bromodomain (BD1) in complex with dual PI3 kinase (PI3K) inhibitor SF2535


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis.

Andrews, F.H.Singh, A.R.Joshi, S.Smith, C.A.Morales, G.A.Garlich, J.R.Durden, D.L.Kutateladze, T.G.

(2017) Proc Natl Acad Sci U S A 114: E1072-E1080

  • DOI: https://doi.org/10.1073/pnas.1613091114
  • Primary Citation of Related Structures:  
    5U28, 5U2C, 5U2E, 5U2F

  • PubMed Abstract: 

    MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.


  • Organizational Affiliation

    Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4
A, B
140Homo 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
837
Query on 837

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
ethyl 4-[5-(morpholin-4-yl)-7-oxo-7H-thieno[3,2-b]pyran-3-yl]benzoate
C20 H19 N O5 S
VRBZWFAUTHKRBB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
837 BindingDB:  5U2E IC50: 277 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.200 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.943α = 90
b = 39.701β = 100.14
c = 62.47γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data 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: 2017-02-08
    Type: Initial release
  • Version 1.1: 2017-03-01
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references