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Discovery and Characterization of Novel Selective Inhibitors of Carbonic Anhydrase IX

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journal contribution
posted on 26.11.2014, 00:00 by Virginija Dudutienė, Jurgita Matulienė, Alexey Smirnov, David D. Timm, Asta Zubrienė, Lina Baranauskienė, Vaida Morku̅naitė, Joana Smirnovienė, Vilma Michailovienė, Vaida Juozapaitienė, Aurelija Mickevičiu̅tė, 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
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 of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound’s co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX’s catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.