Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells
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Justina Kazokaitė1,2, Raymon Niemans2, Virginija Dudutienė1, Holger M. Becker3, Jānis Leitāns4, Asta Zubrienė1, Lina Baranauskienė1, Gabor Gondi5,6, Reinhard Zeidler5,6, Jurgita Matulienė1, Kaspars Tārs1, Ala Yaromina2, Philippe Lambin2, Ludwig J. Dubois2,* and Daumantas Matulis1,*
1Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania
2Department of Radiotherapy (The M-Lab Group), GROW – School for Oncology and Developmental Biology, Maastricht Comprehensive Cancer Centre, Maastricht University Medical Centre, Maastricht, The Netherlands
3Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany
4Latvian Biomedical Research and Study Center, Riga, Latvia
5Department of Gene Vectors, Helmholtz Center for Environmental Health, Munich, Germany
6Department of Otorhinolaryngology, Klinikum der Universität München, Munich, Germany
*These authors are contributed equally to this work
Daumantas Matulis, email: [email protected], [email protected]
Keywords: cancer; hypoxia; drug design; sulfonamide; carbonic anhydrase IX
Received: April 12, 2018 Accepted: May 14, 2018 Published: June 01, 2018
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 IX-specific therapy.
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