Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Abstract

The CA IX is a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. We designed novel compounds that have several functionalities: 1) primary sulfonamide group recognizing carbonic anhydrases (CA), 2) high-affinity moieties specifically recognizing CA IX among all CA isozymes, and 3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification. Our designed prodrug candidates bearing moderately active pre-vinyl sulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CA IX. The lead inhibitors reached 2 pM affinity, highest among known CA IX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site.