Carbonic anhydrase inhibitors: an update on experimental agents for the treatment and imaging of hypoxic tumors

Introduction Hypoxic tumors, unlike normal tissues, overexpress proteins involved in oxygen sensing, metabolism, pH regulation, angiogenesis, immunological response, and other survival mechanisms, which are under investigation as antitumor drug targets.Areas covered Carbonic anhydrase (CA) isoforms CA IX and XII are among these validated antitumor/antimetastatic drug targets, with several of their inhibitors undergoing preclinical or clinical-stage investigations. Alone or in combination with other chemotherapeutic agents or radiotherapy, CA IX/XII inhibitors, such as SLC-0111, SLC-149, S4, 6A10, etc., were shown to inhibit the growth of the primary tumor, metastases, and invasiveness of many tumor types, being also amenable for the development of imaging agents.Expert Opinion SLC-0111 is the most investigated agent, being in Phase Ib/II clinical trials. In addition to its interference with extracellular acidifications, it has been shown to promote ferroptosis in cancer cells, another antitumor mechanism of this compound and the entire class. A large number sulfonamide and non-sulfonamide inhibitors have been developed using SLC-0111 as lead in the last three years, together with hybrid agents incorporating CA inhibitors and other anticancer chemotypes, including cytotoxins, telomerase, thioredoxin or P-glycoprotein inhibitors, adenosine A2A receptor antagonists, pyrophosphatase/phosphodiesterase-3 inhibitors or antimetabolites. All of them showed significant antitumor activity.