6U5M

Discovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report

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This is version 1.3 of the entry. See complete history


Literature

Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.

Macdonald, J.D.Chacon Simon, S.Han, C.Wang, F.Shaw, J.G.Howes, J.E.Sai, J.Yuh, J.P.Camper, D.Alicie, B.M.Alvarado, J.Nikhar, S.Payne, W.Aho, E.R.Bauer, J.A.Zhao, B.Phan, J.Thomas, L.R.Rossanese, O.W.Tansey, W.P.Waterson, A.G.Stauffer, S.R.Fesik, S.W.

(2019) J Med Chem 62: 11232-11259

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b01411
  • Primary Citation of Related Structures:  
    6U5M, 6U5Y, 6U6W, 6U80, 6U8B, 6U8L, 6U8O

  • PubMed Abstract: 

    The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.


  • Organizational Affiliation

    Department of Chemistry , Vanderbilt University , Nashville , Tennessee 37232 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
WD repeat-containing protein 5
A, B
304Homo sapiensMutation(s): 0 
Gene Names: WDR5BIG3
UniProt & NIH Common Fund Data Resources
Find proteins for P61964 (Homo sapiens)
Explore P61964 
Go to UniProtKB:  P61964
PHAROS:  P61964
GTEx:  ENSG00000196363 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61964
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Q0S (Subject of Investigation/LOI)
Query on Q0S

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-bromo-2-hydroxy-N-[3-(methylsulfonyl)-5-(pentafluoro-lambda~6~-sulfanyl)phenyl]benzene-1-sulfonamide
C13 H11 Br F5 N O5 S3
GXKWWSXTDOWSFB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
Q0S Binding MOAD:  6U5M Kd: 511 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.163 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 134.39α = 90
b = 46.672β = 117.3
c = 112.517γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-04
    Type: Initial release
  • Version 1.1: 2019-12-18
    Changes: Database references
  • Version 1.2: 2020-01-08
    Changes: Database references
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description