4CQ0

Cyclic secondary sulfonamides: unusually good inhibitors of cancer- related carbonic anhydrase enzymes


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Cyclic Secondary Sulfonamides: Unusually Good Inhibitors of Cancer-Related Carbonic Anhydrase Enzymes.

Moeker, J.Peat, T.S.Bornaghi, L.F.Vullo, D.Supuran, C.T.Poulsen, S.

(2014) J Med Chem 57: 3522

  • DOI: https://doi.org/10.1021/jm500255y
  • Primary Citation of Related Structures:  
    4CQ0

  • PubMed Abstract: 

    Carbonic anhydrase IX (CA IX) is a target for hypoxic cancer therapies, and the discovery of CA IX selective ligands is imperative for the development of these agents. Primary sulfonamides are broad specificity inhibitors of CA enzymes, while secondary sulfonamides are generally poor CA inhibitors. However, saccharin, a cyclic secondary sulfonamide, has unusually good inhibition of CA IX (Ki = 103 nM). In this study, we demonstrate that the affinity and selectivity of saccharin for CA IX can be further modulated when linked to hydrophobic or hydrophilic substituents. The hydrophilic glycoconjugate derivative (12) showed improved inhibition of CA IX (Ki = 49.5 nM) and extremely poor inhibition of the predominant off-target CAs (Ki > 50000 nM) compared to saccharin. This >1000-fold selectivity for CA IX over off-target CAs is unprecedented for classical primary sulfonamide CA inhibitors. Our study highlights the potential of cyclic secondary sulfonamides to be exploited for the discovery of potent, cancer-selective CA inhibitors.


  • Organizational Affiliation

    Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CARBONIC ANHYDRASE 2260Homo sapiensMutation(s): 0 
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SXS BindingDB:  4CQ0 Ki: 5.00e+4 (nM) from 1 assay(s)
IC50: 4.90e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.183α = 90
b = 41.21β = 104.64
c = 71.919γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-16
    Type: Initial release
  • Version 1.1: 2014-05-07
    Changes: Database references
  • Version 1.2: 2019-05-15
    Changes: Data collection, Experimental preparation, Other
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description