Targeting carbonic anhydrases for the management of hypoxic metastatic tumors

Several isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are connected with tumorigenesis. Hypoxic tumors overexpress CA IX and XII as a consequence of HIF activation cascade, being involved in pH regulation, metabolism, and metastases formation. Other isoforms (CA I, II, III, IV) were also reported to be present in some tumors.

Some CA isoforms are biomarkers for disease progression or response to therapy. Inhibitors, antibodies, and other procedures for targeting these enzymes for the treatment of tumors/metastases are discussed. Sulfonamides and coumarins represent the most investigated classes of inhibitors, but carboxylates, selenium, and tellurium-containing inhibitors were also investigated. Hybrid drugs of CA inhibitors with other antitumor agents for multitargeted therapy were reported.

Targeting CAs present in solid or hematological tumors with selective, targeted inhibitors is a validated approach, which has been consolidated in the last years. A host of new preclinical data and several clinical trials of antibodies and small-molecule inhibitors are ongoing, which connected with the large number of new chemotypes/procedures discovered to be effective, may lead to a breakthrough in this therapeutic area. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2018 to 2023.