Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors
Author(s)
Mahon, Brian P
Hendon, Alex M
Driscoll, Jenna M
Rankin, Gregory M
Poulsen, Sally-Ann
Supuran, Claudiu T
McKenna, Robert
Griffith University Author(s)
Year published
2015
Metadata
Show full item recordAbstract
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.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.
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Journal Title
Bioorganic and Medicinal Chemistry Letters
Volume
23
Issue
4
Subject
Medicinal and biomolecular chemistry
Medicinal and biomolecular chemistry not elsewhere classified
Organic chemistry
Pharmacology and pharmaceutical sciences