Journal Article

PUBDB-2015-00005

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Discovery and Characterization of Novel Selective Inhibitors of Carbonic Anhydrase IX

Dudutienė, V. ; Matulienė, J. ; Smirnov, A.>Extern* ; Timm, D. D. ; Zubrienė, A. ; Baranauskienė, L. ; Morku̅naitė, V. ; Smirnovienė, J. ; Michailovienė, V. ; Juozapaitienė, V. ; Mickevičiu̅tė, A. ; Kazokaitė, J. ; Bakšytė, S. ; Kasiliauskaitė, A. ; Jachno, J. ; Revuckienė, J. ; Kišonaitė, M. ; Pilipuitytė, V. ; Ivanauskaitė, E. ; Milinavičiu̅tė, G. ; Smirnovas, V. ; Petrikaitė, V. ; Kairys, V. ; Petrauskas, V. ; Norvaišas, P. ; Lingė, D. ; Gibieža, P. ; Čapkauskaitė, E. ; Zakšauskas, A. ; Kazlauskas, E. ; Manakova, E.>Extern* ; Gražulis, S.>Extern* ; Ladbury, J. E. ; Matulis, D. (Corresponding author)

2014
ACS Washington, DC

This record in other databases:        

Please use a persistent id in citations: doi:10.1021/jm501003k

Abstract: 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.

Note: (c) American Chemical Society. Post referee full text in progress. Embargo for full text 1 year from October 30, 2014.

---

Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. PETRA Beamline P13 (POF2-54G14) (POF2-54G14)
2. PETRA Beamline P14 (POF2-54G14) (POF2-54G14)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2014

---

Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---