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J Med Chem. 2015 Aug 27;58(16):6630-8. doi: 10.1021/acs.jmedchem.5b00845. Epub 2015 Aug 13.

Mapping Selective Inhibition of the Cancer-Related Carbonic Anhydrase IX Using Structure-Activity Relationships of Glucosyl-Based Sulfamates.

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Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , 1600 SW Archer Road, PO Box 100245, Gainesville, Florida 32610, United States.
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.


Inhibition of human carbonic anhydrase IX (hCA IX) has shown to be therapeutically advantageous for treating many types of highly aggressive cancers. However, designing selective inhibitors for hCA IX has been difficult due to its high structural homology and sequence similarity with off-target hCAs. Recently, the use of glucosyl sulfamate inhibitors has shown promise as selective inhibitors for hCA IX. In this study, we present five X-ray crystal structures, determined to a resolution of 1.7 Ã… or better, of both hCA II (a ubiquitous CA) and an engineered hCA IX-mimic in complex with selected glucosyl sulfamates and structurally rationalize mechanisms for hCA IX selectivity. Results from this study have allowed us, for the first time, to empirically "map" key interactions of the hCA IX active site in order to establish parameters needed to design novel hCA IX selective inhibitors.

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