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

J. Kazokaite, Raymon Niemans, V. Dudutiene, Holger M. Becker, J. Leitans, A. Zubriene, L. Baranauskiene, Gabor Gondi, Reinhard Zeidler, J. Matuliene, K. Tars, Ala Yaromina, Philippe Lambin, Ludwig Dubois, D. Matulis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Original languageEnglish
Pages (from-to)26800-26816
Issue number42
Publication statusPublished - 2018

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