5F25

Crystal structure of the BRD9 bromodomain in complex with compound 4.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor.

Martin, L.J.Koegl, M.Bader, G.Cockcroft, X.L.Fedorov, O.Fiegen, D.Gerstberger, T.Hofmann, M.H.Hohmann, A.F.Kessler, D.Knapp, S.Knesl, P.Kornigg, S.Muller, S.Nar, H.Rogers, C.Rumpel, K.Schaaf, O.Steurer, S.Tallant, C.Vakoc, C.R.Zeeb, M.Zoephel, A.Pearson, M.Boehmelt, G.McConnell, D.

(2016) J Med Chem 59: 4462-4475

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01865
  • Primary Citation of Related Structures:  
    5EU1, 5F1H, 5F1L, 5F25, 5F2P

  • PubMed Abstract: 

    Components of the chromatin remodelling switch/sucrose nonfermentable (SWI/SNF) complex are recurrently mutated in tumors, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold. Crystallographic information on the inhibitors bound to BRD9 guided their development with respect to potency for BRD9 and selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular function and display antitumor activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.


  • Organizational Affiliation

    Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BRD9
A, B
123Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H8M2 (Homo sapiens)
Explore Q9H8M2 
Go to UniProtKB:  Q9H8M2
PHAROS:  Q9H8M2
GTEx:  ENSG00000028310 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H8M2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5TU
Query on 5TU

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-(1,5-dimethyl-6-oxidanylidene-pyridin-3-yl)benzamide
C14 H14 N2 O2
LCFYRSDVZKRXGW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5TU BindingDB:  5F25 Kd: 9100 (nM) from 1 assay(s)
IC50: 9338 (nM) from 1 assay(s)
Binding MOAD:  5F25 Kd: 9100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.038α = 90
b = 125.017β = 90
c = 29.941γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-09
    Type: Initial release
  • Version 1.1: 2016-06-08
    Changes: Database references
  • Version 2.0: 2024-01-10
    Changes: Atomic model, Data collection, Database references, Refinement description