Aivaras Vaškevičius, Denis Baronas, Janis Leitans, Agnė Kvietkauskaitė, Audronė Rukšėnaitė, Elena Manakova, Zigmantas Toleikis, Algirdas Kaupinis, Andris Kazaks, Marius Gedgaudas, Aurelija Mickevičiūtė, Vaida Juozapaitienė, Helgi B Schiöth, Kristaps Jaudzems, Mindaugas Valius, Kaspars Tars, Saulius Gražulis, Franz-Josef Meyer-Almes, Jurgita Matulienė, Asta Zubrienė, Virginija Dudutienė, Daumantas Matulis
bioRxiv 2024
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.
