Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site

Abstract

Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to produce bicarbonate and a proton. Multiple CA isoforms are implicated in a range of diseases, including cancer. In solid tumors, continuously dividing cells create hypoxic conditions that eventually lead to an acidic microenvironment. Hypoxic tumor cells have different mechanisms in place to regulate and adjust the surrounding microenvironment for survival. These mechanisms include expression of CA isoform IX (CA IX) and XII (CA XII). These enzymes help maintain a physiological intracellular pH while simultaneously contributing to an acidic extracellular pH, leading to tumor cell survival. Expression of CA IX and CA XII has also been shown to promote tumor cell invasion and metastasis. This review discusses the characteristics of CA IX and CA XII, their mechanism of action, and validates their prospective use as anticancer targets. We discuss the current status of small inhibitors that target these isoforms, both classical and non-classical, and their future design in order to obtain isoform-specificity for CA IX and CA XII. Biologics, such as monoclonal antibodies, monoclonal-radionuclide conjugated chimeric antibodies, and antibody-small molecule conjugates are also discussed.

Kinetic Study of CO2 Hydration by Small-Molecule Catalysts with A Second Coordination Sphere that Mimic the Effect of the Thr-199 Residue of Carbonic Anhydrase

“…Therefore, it was concluded that the structural effect had a more significant impact on the pK a . The deprotonated structure of (2) can be deduced from that of CA [42,43]. It can be deduced that the O atom of the hydroxyl substituent at position two of the pyridine unit and the H atom of the Zn-bound hydroxide ion form a hydrogen bond to stabilize the structure.…”

Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells

“…Specific interference with tumor H + dynamics (pH i and pH e ) and/or upregulated glycolytic metabolism may be an important step towards reversing the disrupted pH gradient and better treatment of solid tumors [9,46]. This approach has been made in a number of pre-clinical and also clinical studies by buffer/bicarbonate therapy [47,48], targeting pH regulating transporters and carbonic anhydrases [49] and pH-sensitive drug delivery systems [46]. Among these, PPIs are supposedly in the most advanced stages of clinical trials for prostate, colorectal and esophageal cancer [46,50], and it is presumed that they interact with cysteines of V-ATPases and other lysosomal and plasma membrane proteins.…”

A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

“…Our lab, and others, have also hypothesized that CA IX serves to regulate pH e by responding to changes in substrate concentration (10,19,20). As pH e decreases, CA IX sequesters protons in the form of CO 2 and H 2 O through the dehydration reaction (27,32,33). As pH e increases CA IX produces HCO 3 and H + via the hydration reaction (27,33).…”