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Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors.

ABSTRACT: Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.

SUBMITTER: Mahon BP

PROVIDER: S-EPMC4352949 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors.

Mahon Brian P BP Hendon Alex M AM Driscoll Jenna M JM Rankin Gregory M GM Poulsen Sally-Ann SA Supuran Claudiu T CT McKenna Robert R

Bioorganic & medicinal chemistry 20141223 4

Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are pre ...[more]

PMID: 25614109

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