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

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 Å 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.