title: Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors.
abstract: Carbonic anhydrase (CA) enzymes, specifically membrane-bound isozymes CA IX and CA XII, underpin a pH-regulating system that enables hypoxic tumor cell survival and proliferation. CA IX and XII are implicated as potential targets for the development of new hypoxic cancer therapies. To date, only a few small molecules have been characterized in CA-relevant cell and animal model systems. In this paper, we describe the development of a new class of carbohydrate-based small molecule CA inhibitors, many of which inhibit CA IX and XII within a narrow range of low nanomolar K(i) values (5.3-11.2 nM). We evaluate for the first time carbohydrate-based CA inhibitors in cell-based models that emulate the protective role of CA IX in an acidic tumor microenvironment. Our findings identified two inhibitors (compounds 5 and 17) that block CA IX-induced survival and have potential for development as in vivo cancer cell selective inhibitors.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Morris
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.forename: Caroline
authors.initials: C
authors.lastname: Grellier
authors.forename: Marie
authors.initials: M
authors.lastname: Lopez
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Bornaghi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D004354:Drug Screening Assays, Antitumor; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D005960:Glucosides; D007527:Isoenzymes; D013449:Sulfonamides; C568517:4-(4-((2',3',4',6'-tetra-O-acetylglucopyranosyl)thiomethyl)-5-iodo-1-H-1,2,3-triazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C568518:4-(4-((glucopyranosyl)thiomethyl)-5-iodo-1-H-1,2,3-triazol-1-yl)benzenesulfonamide; C089226:CA9 protein, human; C477378:carbonic anhydrase XII