Human carbonic anhydrase IX (CAIX) is a transmembrane zinc metalloenzyme catalyzing the extracellular conversion of CO2 and H2O into HCO3- and H+. CAIX expression in advanced tumors maintains optimal intracellular and extracellular pH and promotes cancer cell survival, migration, and metastasis. The proposed project will combine expertise in structural biology, medicinal chemistry, and cancer biology to study the intrinsically disordered proteoglycan-like (PG) domain of CAIX that is functionally essential but poorly characterized. We will use state-of-the-art solution NMR spectroscopy and structural biology approaches to study the PG domain. Subsequent SPR binding analyses will identify its critical structural determinants. Informed by the structural studies and molecular modeling results, the medicinal chemistry group will synthesize novel 1,3,5-triazine derivatives as specific CAIX inhibitors, followed by in vitro activity testing. Analyses of the PG domain contribution to CAIX activity and molecular interactions in the context of cancer cells and the new compound's biological activity under conditions representing different bioenergetic/metabolic contexts found in advanced tumors will complement the whole process. This approach will identify the biologically most active compounds and determine conditions that make cancer cells highly susceptible to CAIX inhibition.

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