Trends in drug discovery for carbonic anhydrases: FDA approvals, clinical trials, molecular functions, and...

Human carbonic anhydrases (CAs) catalyse the rapid conversion of CO₂ and bicarbonate, supporting pH balance, ion transport and many metabolic processes. All 15 human CA family proteins share a conserved structure, but they differ in activity, localisation and tissue distribution. Several CA isozymes are directly linked to distinct clinical conditions. Although CA-inhibiting drugs have long been clinically used, research across individual isozymes, chemical compound classes, and therapeutic uses has progressed unevenly. This review brings together current structural, biochemical and pharmacological knowledge of human CAs. It summarises catalytic properties, expression patterns and disease associations across the isozyme family. Loss-of-function variants in CA II and CA VA cause well-defined inherited metabolic disorders. At the same time, the strong and selective overexpression of CA IX and CA XII in tumours provides clear targets for cancer therapy. We outline the development of CA-directed drugs, from early non-selective sulphonamides to modern treatments used in ophthalmology, neurology and metabolic medicine. We also review ongoing clinical trials of isozyme-selective small molecules, antibodies, and radiopharmaceuticals, with particular focus on CA IX-targeting agents. Classical sulphonamides inhibit CAs by binding the catalytic zinc ion and displacing the Zn-bound water. Newer inhibitors achieve selectivity by engaging isozyme-specific pockets and surrounding regions. Antibody- and small-molecule-based radiolabelled ligands targeting CA IX are now advancing as promising tools for precision oncology, with several candidates demonstrating excellent clinical trial results and entering late-stage clinical development.