Home > Publications database > Discovery and Characterization of Novel Selective Inhibitors of Carbonic Anhydrase IX > print

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024 7 _ |a 10.1021/jm501003k
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024 7 _ |a 0095-9065
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024 7 _ |a 1520-4804
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100 1 _ |a Dudutienė, Virginija
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245 _ _ |a Discovery and Characterization of Novel Selective Inhibitors of Carbonic Anhydrase IX
260 _ _ |a Washington, DC
|c 2014
|b ACS
336 7 _ |a Journal Article
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336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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500 _ _ |a (c) American Chemical Society. Post referee full text in progress. Embargo for full text 1 year from October 30, 2014.
520 _ _ |a Human carbonic anhydrase IX (CA IX) is highly expressedin tumor tissues, and its selective inhibition provides a potential target forthe treatment of numerous cancers. Development of potent, highlyselective inhibitors against this target remains an unmet need in anticancertherapeutics. A series of fluorinated benzenesulfonamides with sub-stituents on the benzene ring was designed and synthesized. Several ofthese exhibited a highly potent and selective inhibition profile against CAIX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of thebenzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into thehydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound’s co-crystal structure with chimeric CAIX. 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. Thecompound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described inthis work provide the basis for novel anticancer therapeutics targeting CA IX.
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700 1 _ |a Matulienė, Jurgita
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700 1 _ |a Smirnov, Alexey
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700 1 _ |a Timm, David D.
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700 1 _ |a Zubrienė, Asta
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700 1 _ |a Baranauskienė, Lina
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700 1 _ |a Morku̅naitė, Vaida
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700 1 _ |a Gražulis, Saulius
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700 1 _ |a Ladbury, John E.
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700 1 _ |a Matulis, Daumantas
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773 _ _ |a 10.1021/jm501003k
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