Aryl Sulfamates Get a Systematic SAR Look as Carbonic Anhydrase IX Binders
- Ortho- and meta-substituted aryl sulfamates were synthesized and profiled by thermal shift, enzyme inhibition and a live-cell competition assay against CA IX, the isozyme overexpressed in hypoxic solid tumors.
- The best compounds bound CA IX with very high affinity, and X-ray structures with several isozymes identified the groups driving affinity and selectivity.
- pH-dependent binding data indicate the deprotonated, negatively charged sulfamate nitrogen coordinates the active-site zinc.
💡 Points
CA inhibitors are dominated by sulfonamides, so a clean sulfamate SAR backed by crystal structures is useful chemotype diversification. Selectivity over the ubiquitous CA I and II is what sinks tumor-CA programs, and the co-crystals give a concrete handle on it. Live-cell competition data beat purely recombinant assays, but I'd want hypoxic-cell potency and physicochemical properties before calling these lead-like.
Structure-Affinity and Selectivity of Aryl-Sulfamates as Inhibitors of Carbonic Anhydrase IX ↗