Discovery and Characterization of Novel Selective Inhibitors of Carbonic Anhydrase IX

• DOI: 10.1021/jm501003k
• Publication Date: 2014-10-30T16:42:04Z
• Authors: Virginija Dudutienė; Jurgita Matulienė; Alexey Smirnov; David D. Timm; Asta Zubrienė; Lina Baranauskienė; Vaida Morku̅naitė; Joana Smirnovienė; Vilma Michailovienė; Vaida Juozapaitienė; Aurelija Mickevič...; Justina Kazokaitė; Sandra Bakšytė; Aistė Kasiliauskaitė; Jelena Jachno; Jurgita Revuckienė; Miglė Kišonaitė; Vilma Pilipuitytė; Eglė Ivanauskaitė; Goda Milinavičiu̅tė; Vytautas Smirnovas; Vilma Petrikaitė; Visvaldas Kairys; Vytautas Petrauskas; Povilas Norvaišas; Darius Lingė; Paulius Gibieža; Edita Čapkauskaitė; Audrius Zakšauskas; Egidijus Kazlauskas; Elena Manakova; Saulius Gražulis; John E. Ladbury; Daumantas Matulis
• Keywords: Carbonic anhydrase II; Sulfonamide; Structure–activity relationship

Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development potent, inhibitors against this remains an unmet need anticancer therapeutics. A series fluorinated benzenesulfonamides with substituents on benzene ring was designed synthesized. Several these exhibited potent profile CA IX. Three fluorine atoms significantly increased affinity by withdrawing electrons lowering pKa benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into hydrophobic pocket active site but not II, shown compound's co-crystal structure chimeric strongest inhibitor recombinant human IX's catalytic domain cells achieved 50 pM. However, high diminished selectivity. most compound 10 nM affinity. that showed best balance between selectivity bound 1 described work provide basis novel therapeutics targeting