6YQR

BRD9 with Biphenyl-methylamino-dimethylpyridazinone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.152 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Application of Atypical Acetyl-lysine Methyl Mimetics in the Development of Selective Inhibitors of the Bromodomain-Containing Protein 7 (BRD7)/Bromodomain-Containing Protein 9 (BRD9) Bromodomains.

Clegg, M.A.Bamborough, P.Chung, C.W.Craggs, P.D.Gordon, L.Grandi, P.Leveridge, M.Lindon, M.Liwicki, G.M.Michon, A.M.Molnar, J.Rioja, I.Soden, P.E.Theodoulou, N.H.Werner, T.Tomkinson, N.C.O.Prinjha, R.K.Humphreys, P.G.

(2020) J Med Chem 63: 5816-5840

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c00075
  • Primary Citation of Related Structures:  
    6YQR, 6YQS, 6YQW, 6YQZ

  • PubMed Abstract: 

    Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the n -butyl group as an atypical KAc methyl mimetic allowed generation of 31 (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The n -butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.


  • Organizational Affiliation

    GlaxoSmithKline R&D, Stevenage SG1 2NY, Hertfordshire, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 9A [auth AAA]106Homo sapiensMutation(s): 0 
Gene Names: BRD9UNQ3040/PRO9856
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P8W (Subject of Investigation/LOI)
Query on P8W

Download Ideal Coordinates CCD File 
B [auth AAA]2,4-dimethyl-5-[(2-phenylphenyl)methylamino]pyridazin-3-one
C19 H19 N3 O
JLOICACPNWZYGI-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.152 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 24.524α = 71.007
b = 33.885β = 74.35
c = 39.614γ = 74.205
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2021-03-24 
  • Deposition Author(s): Chung, C.

Revision History  (Full details and data files)

  • Version 1.0: 2021-03-24
    Type: Initial release
  • Version 1.1: 2024-05-15
    Changes: Data collection, Database references, Derived calculations