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Kazokaite, J.* ; Niemans, R.* ; Dudutiene, V.* ; Becker, H.M.* ; Leitans, J.* ; Zubriene, A.* ; Baranauskiene, L.* ; Gondi, G. ; Zeidler, R. ; Matuliene, J.* ; Tars, K.* ; Yaromina, A.* ; Lambin, P.* ; Dubois, L.J.* ; Matulis, D.*

Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells.

Oncotarget 9, 26800-26816 (2018)
Verlagsversion Forschungsdaten DOI PMC
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Creative Commons Lizenzvertrag
Human carbonic anhydrase (CA) IX has emerged as a promising anticancer target and a diagnostic biomarker for solid hypoxic tumors. Novel fluorinated CA IX inhibitors exhibited up to 50 pM affinity towards the recombinant human CA IX, selectivity over other CAs, and direct binding to Zn(II) in the active site of CA IX inducing novel conformational changes as determined by X-ray crystallography. Mass spectrometric gas-analysis confirmed the CA IX-based mechanism of the inhibitors in a CRISPR/Cas9-mediated CA IX knockout in HeLa cells. Hypoxia-induced extracellular acidification was significantly reduced in HeLa, H460, MDA-MB-231, and A549 cells exposed to the compounds, with the IC50 values up to 1.29 nM. A decreased clonogenic survival was observed when hypoxic H460 3D spheroids were incubated with our lead compound. These novel compounds are therefore promising agents for CA IXspecific therapy.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cancer ; Carbonic Anhydrase Ix ; Drug Design ; Hypoxia ; Sulfonamide
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Zeitschrift OncoTarget
Quellenangaben Band: 9, Heft: 42, Seiten: 26800-26816 Artikelnummer: , Supplement: ,
Verlag Impact Journals LLC
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-001
DOI 10.18632/oncotarget.25508
Scopus ID 85047856824
PubMed ID 29928486
Erfassungsdatum 2018-07-12
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