The structural basis for the selectivity of sulfonamide-based inhibitors of carbonic anhydrase isoforms IX and XII: A comprehensive review of the crystallographic data

Hypoxia, a shortage of oxygen arising from a cancer tumour’s inability to sufficiently vascularize in response to the metabolic demands, reliably alters the regulation of an array of genes in solid cancers, including the significant upregulation of carbonic anhydrases (CAs). CAs are a ubiquitously expressed family of zinc-dependent metalloenzymes that maintain pH homeostasis by catalyzing the interconversion of carbon dioxide and water to bicarbonate and protons. Most of the 15 human α-CA isozymes are overexpressed in cancers, but CA IX and CA XII in particular have expression profiles that make them both promising diagnostic and prognostic candidates, and putative anticancer drug targets as their inhibition in healthy tissue is likely tolerated; however, it is a daunting task to design inhibitors selective for these two cancer-associated CAs due to the high structural similarity among all the human CAs, and the dangers inherent in pan-CA inhibition. Fortunately, this is becoming feasible with the accumulation of structural information arising from crystallography and Cryo-EM experiments—unfortunately, this data must be curated by the researcher as it is not analyzed in a single place. This review addresses this problem by discussing all available crystal data of ligand-cocrystallized CA IX and CA XII, and then juxtaposes these structures with those of CA II (the ubiquitous CA) complexes to better understand what features lend themselves to ligand specificity. The resulting comparative analysis of the 64 X-ray structures of sulfonamides cocrystallized with CA II, CA IX, and CA XII can help focus attention on promising avenues of future experimentation.