Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors. Issue 4 (15th February 2015)

• Record Type: Journal Article
• Authors: Mahon, Brian P.; Hendon, Alex M.; Driscoll, Jenna M.; Rankin, Gregory M.; Poulsen, Sally-Ann; Supuran, Claudiu T.; McKenna, Robert
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 4(2015)
• Page Start: 849
• Page End: 854
• Publication Date: 2015-02-15
• Subjects: CA carbonic anhydrase -- Ki inhibition constant -- ZBG zinc binding group; Saccharin -- Metalloenzyme -- Carbonic anhydrase IX -- CA IX-mimic -- Structure-based drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2014.12.030
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 forSAC and >1000-fold whenSAC is conjugated to a carbohydrate moiety). The X-ray crystal structures ofSAC 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 ofSAC selective CA isoform inhibition.