title: Structure activity study of carbonic anhydrase IX: Selective inhibition with ureido-substituted benzenesulfonamides.
abstract: Ureido-substituted benzenesulfonamides (USBs) show great promise as selective and potent inhibitors for human carbonic anhydrase hCA IX and XII, with one such compound (SLC-0111/U-F) currently in clinical trials (clinical trials.gov, NCT02215850). In this study, the crystal structures of both hCA II (off-target) and an hCA IX-mimic (target) in complex with selected USBs (U-CH3, U-F, and U-NO2), at resolutions of 1.9 Å or better, are presented, and demonstrate differences in the binding modes within the two isoforms. The presence of residue Phe 131 in hCA II causes steric hindrance (U-CH3, 1765 nM; U-F, 960 nM; U-NO2, 15 nM) whereas in hCA IX (U-CH3, 7 nM; U-F, 45 nM; U-NO2, 1 nM) and hCA XII (U-CH3, 6 nM; U-F, 4 nM; U-NO2, 6 nM), 131 is a Val and Ala, respectively, allows for more favorable binding. Our results provide insight into the mechanism of USB selective inhibition and useful information for structural design and drug development, including synthesis of hybrid USB compounds with improved physiochemical properties.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Mam Y
authors.initials: MY
authors.lastname: Mboge
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Mahon
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lamas
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Lillien
authors.initials: L
authors.lastname: Socorro
authors.affiliation: University of Florence, NEUROFARBA Department, Sezione di Farmaceutica e Nutraceutica, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.affiliation: University of Florence, NEUROFARBA Department, Sezione di Farmaceutica e Nutraceutica, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Frost
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA. Electronic address: rmckenna@ufl.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
mesh_terms: D001665:Binding Sites; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives*; D000096926:Benzenesulfonamides
chemical_list: D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D014508:Urea; D000096926:Benzenesulfonamides
keywords: Benzenesulfonamides; Cancer therapy; Carbonic anhydrase IX; Structure-activity relationships; X-ray crystallography; hCA IX-Mimic