Structural insights into carbonic anhydrase IX isoform specificity of carbohydrate-based sulfamates

J Med Chem. 2014 Oct 23;57(20):8635-45. doi: 10.1021/jm5012935. Epub 2014 Oct 8.


Carbonic anhydrase IX (CA IX) is an extracellular transmembrane homodimeric zinc metalloenzyme that has been validated as a prognostic marker and therapeutic target for several types of aggressive cancers. CA IX shares a close homology with other CA isoforms, making the design of CA IX isoform selective inhibitors challenging. In this paper, we describe the development of a new class of CA IX inhibitors that comprise a sulfamate as the zinc binding group, a variable linker, and a carbohydrate "tail" moiety. Seven compounds inhibited CA IX with low nM Ki values of 1-2 nM and also exhibited permeability profiles to preferentially target the binding of extracellular CA IX over cytosolic CAs. The crystal structures of two of these compounds in complex with a CA IX-mimic (a variant of CA II, with active site residues that mimic CA IX) and one compound in complex with CA II have been determined to 1.7 Å resolution or better and demonstrate a selective mechanism of binding between the hydrophilic and hydrophobic pockets of CA IX versus CA II. These compounds present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry*
  • Antigens, Neoplasm / metabolism*
  • Biomarkers, Tumor / chemistry
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / chemistry*
  • Carbonic Anhydrases / metabolism*
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology
  • Sulfonic Acids / chemistry*


  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Carbonic Anhydrase Inhibitors
  • Small Molecule Libraries
  • Sulfonic Acids
  • sulfamic acid
  • Carbonic Anhydrase II
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases

Associated data

  • PDB/4R59
  • PDB/4R5A
  • PDB/4R5B