title: Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of Glucosyl-Based Sulfamates.
abstract: Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 Å or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically "map" key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Mahon
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Lomelino
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Janina
authors.initials: J
authors.lastname: Ladwig
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rankin
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Driscoll
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
authors.forename: Antonieta L
authors.initials: AL
authors.lastname: Salguero
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pinard
authors.affiliation: Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
mesh_terms: D000951:Antigens, Neoplasm / Q000187:drug effects*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013451:Sulfonic Acids; C005741:sulfamic acid; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases