Small molecules and monoclonal antibodies as selective hCA XII inhibitors: An update

A plethora of membrane proteins (ion transporters, carbonic anhydrases) cooperate for the modulation of intra- and extracellular pH in hypoxic cancer cells, among which two carbonic anhydrase (CA) isoforms, CA IX and XII. Similar to human (h) hCA IX, the overexpression of hCA XII has been registered in some cancer cells and its role emerged as a marker as well as a therapeutic target for fighting chemoresistance, together with efflux pumps. In this chapter, we focus our attention on the most recent discoveries in the design of selective hCA XII inhibitors as theragnostics that could interfere with tumor pH regulation and reduce tumoral and metastatic potential. The structural requirements to achieve isoform selectivity as well as molecular modeling studies will be also discussed. Starting from in vitro assays and following to translational results we discuss available in cell-based assays, the few in vivo systems disclosed so far and their correlations with the biological (animal) data available for CA XII small molecule or antibody inhibitors.