6FE1

Three dimensional structure of human carbonic anhydrase IX in complex with benzenesulfonamide.

Summary for 6FE1

• Entry DOI: 10.2210/pdb6fe1/pdb
• Descriptor: Carbonic anhydrase 9, ZINC ION, 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 114730.33

Authors

Leitans, J.,Tars, K. (deposition date: 2017-12-28, release date: 2018-07-04, Last modification date: 2024-10-16)

Primary citation

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

PubMed Abstract: 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 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.

PubMed: 29928486
DOI: 10.18632/oncotarget.25508

Experimental method

X-RAY DIFFRACTION (1.95 Å)