Anticancer carbonic anhydrase inhibitors: a patent and literature update 2018-2022

INTRODUCTION: Cancer affects an increasing number of patients each year with an unacceptable death toll worldwide. A new therapeutic approach to combat tumors consists in targeting human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII, which are tumor-associated, overexpressed enzymes in hypoxic tumors, being involved in metabolism, pH regulation, ferroptosis, and overall tumor progression. AREAS COVERED: Small molecule hCA IX/XII and antibody drug conjugate inhibitors targeting the two enzymes and their applications in the management of cancer are discussed. EXPERT OPINION: The available 3D crystal structures of hCA IX, XII as well as the off target isoforms hCA I and II, afforded structure-based drug design opportunities, which led to the development of various isoform-selective small molecule inhibitors belonging to diverse classes (sulfonamides, sulfamates, benzoxaboroles, selenols, coumarins, sulfocoumarins, and isocoumarins). Many patents focused on small inhibitors containing sulfonamide/sulfamide/sulfamide derivatives as well as hybrids incorporating sulfonamides and different antitumor chemotypes, such as cytotoxic drugs, kinase/telomerase inhibitors, P-gp and thioredoxin inhibitors. The most investigated candidate belonging to the class is the sulfonamide SLC-0111, in Phase Ib/II clinical trials for the management of advanced, metastatic solid tumors.