title: Structural insights into carbonic anhydrase IX isoform specificity of carbohydrate-based sulfamates.
abstract: 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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Janina
authors.initials: J
authors.lastname: Moeker
authors.forename: Brian P
authors.initials: BP
authors.lastname: Mahon
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Bornaghi
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000737:chemistry; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002257:Carbonic Anhydrase Inhibitors; D054852:Small Molecule Libraries; D013451:Sulfonic Acids; C005741:sulfamic acid; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases