6F3B

Crystal structure of human carbonic anhydrase I in complex with the 1-(2-hydroxy-5-sulfamoylphenyl)-3-[(4-methylphenyl)methyl]urea inhibitor

Summary for 6F3B

• Entry DOI: 10.2210/pdb6f3b/pdb
• Descriptor: Carbonic anhydrase 1, ZINC ION, 1-[(4-methylphenyl)methyl]-3-(2-oxidanyl-5-sulfamoyl-phenyl)urea, ... (6 entities in total)
• Functional Keywords: lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 59008.32

Authors

Ferraroni, M.,Supuran, C.T.,Chiapponi, D.,Bozdag, M. (deposition date: 2017-11-28, release date: 2018-10-10, Last modification date: 2024-01-17)

Primary citation

Bozdag, M.,Carta, F.,Ceruso, M.,Ferraroni, M.,McDonald, P.C.,Dedhar, S.,Supuran, C.T.
Discovery of 4-Hydroxy-3-(3-(phenylureido)benzenesulfonamides as SLC-0111 Analogues for the Treatment of Hypoxic Tumors Overexpressing Carbonic Anhydrase IX.
J. Med. Chem., 61:6328-6338, 2018

PubMed Abstract: Herein we report the 2-aminophenol-4-sulfonamide 1 and its ureido derivatives 2-23 as inhibitors of the carbonic anhydrase (CA, EC 4.2.1.1) enzymes as analogues of the hypoxic tumor phase II entering drug SLC-0111. This scaffold may determine preferential rotational isomers to selectively interact within the tumor-associated CAs. Most of the compounds indeed showed in vitro selective inhibition of the tumor associated CA isoforms IX and XII. The most potent derivative within the series was 11 ( Ks of 2.59 and 7.64 nM on hCA IX and XII, respectively), which shares the 4-fluorophenylureido tail with the clinical candidate. We investigated by means of X-ray crystallographic studies the binding modes of three selected compounds of this series to CA I. The evaluation of therapeutic efficacy of compound 11 in an orthotopic, syngeneic model of CA IX-positive breast cancer in vivo showed close matching antitumoral effects and tolerance with SLC-0111.

PubMed: 29962205
DOI: 10.1021/acs.jmedchem.8b00770

Experimental method

X-RAY DIFFRACTION (1.4 Å)