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@ARTICLE{Dudutien:205428,
      author       = {Dudutienė, Virginija and Matulienė, Jurgita and Smirnov,
                      Alexey and Timm, David D. and Zubrienė, Asta and
                      Baranauskienė, Lina and Morku̅naitė, Vaida and
                      Smirnovienė, Joana and Michailovienė, Vilma and
                      Juozapaitienė, Vaida and Mickevičiu̅tė, Aurelija and
                      Kazokaitė, Justina and Bakšytė, Sandra and
                      Kasiliauskaitė, Aistė and Jachno, Jelena and Revuckienė,
                      Jurgita and Kišonaitė, Miglė and Pilipuitytė, Vilma and
                      Ivanauskaitė, Eglė and Milinavičiu̅tė, Goda and
                      Smirnovas, Vytautas and Petrikaitė, Vilma and Kairys,
                      Visvaldas and Petrauskas, Vytautas and Norvaišas, Povilas
                      and Lingė, Darius and Gibieža, Paulius and Čapkauskaitė,
                      Edita and Zakšauskas, Audrius and Kazlauskas, Egidijus and
                      Manakova, Elena and Gražulis, Saulius and Ladbury, John E.
                      and Matulis, Daumantas},
      title        = {{D}iscovery and {C}haracterization of {N}ovel {S}elective
                      {I}nhibitors of {C}arbonic {A}nhydrase {IX}},
      journal      = {Journal of medicinal chemistry},
      volume       = {57},
      number       = {22},
      issn         = {1520-4804},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {PUBDB-2015-00005},
      pages        = {9435 - 9446},
      year         = {2014},
      note         = {(c) American Chemical Society. Post referee full text in
                      progress. Embargo for full text 1 year from October 30,
                      2014.},
      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.},
      cin          = {EMBL-User},
      ddc          = {540},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {PETRA Beamline P13 (POF2-54G14) / PETRA Beamline P14
                      (POF2-54G14)},
      pid          = {G:(DE-H253)POF2-P13-20130405 /
                      G:(DE-H253)POF2-P14-20130405},
      experiment   = {EXP:(DE-H253)P-P13-20150101 / EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000345722200015},
      pubmed       = {pmid:25358084},
      doi          = {10.1021/jm501003k},
      url          = {https://bib-pubdb1.desy.de/record/205428},
}