Discovery and Characterization of Novel Selective Inhibitors of Carbonic Anhydrase IX
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- 作者：Virginija Dudutien臈 ; Jurgita Matulien臈 ; Alexey Smirnov ; David D. Timm ; Asta Zubrien臈 ; Lina Baranauskien臈 ; Vaida Morku虆nait臈 ; Joana Smirnovien臈 ; Vilma Michailovien臈 ; Vaida Juozapaitien臈 ; Aurelija Mickevi膷iu虆t臈 ; Justina Kazokait臈 ; Sandra Bak拧yt臈 ; Aist臈 Kasiliauskait臈 ; Jelena Jachno ; Jurgita Revuckien臈 ; Migl臈 Ki拧onait臈 ; Vilma Pilipuityt臈 ; Egl臈 Ivanauskait臈 ; Goda Milinavi膷iu虆t臈 ; Vytautas Smirnovas ; Vilma Petrikait臈 ; Visvaldas Kairys ; Vytautas Petrauskas ; Povilas Norvai拧as ; Darius Ling臈 ; Paulius Gibie啪a ; Edita 膶apkauskait臈 ; Audrius Zak拧auskas ; Egidijus Kazlauskas ; Elena Manakova ; Saulius Gra啪ulis ; John E. Ladbury ; Daumantas Matulis
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：November 26, 2014
- 年：2014
- 卷：57
- 期：22
- 页码：9435-9446
- 全文大小：627K
- ISSN：1520-4804
文摘
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鈥檚 co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX鈥檚 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.