Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that regulates pH in hypoxic tumors and promotes tumor cell survival. Its expression is associated with the occurrence of metastases and poor prognosis. Here, we present nine derivatives of the cobalt bis(dicarbollide)(1-) anion substituted at the boron or carbon sites by alkysulfamide group(s) as highly specific and selective inhibitors of CAIX. Interactions of these compounds with the active site of CAIX were explored on the atomic level using protein crystallography. Two selected derivatives display subnanomolar or picomolar inhibition constants and high selectivity for the tumor-specific CAIX over cytosolic isoform CAII. Both derivatives had a time-dependent effect on the growth of multicellular spheroids of HT-29 and HCT116 colorectal cancer cells, facilitated penetration and/or accumulation of doxorubicin into spheroids, and displayed low toxicity and showed promising pharmacokinetics and a significant inhibitory effect on tumor growth in syngenic breast 4T1 and colorectal HT-29 cancer xenotransplants.

Cancer Research Czech Republic Hněvotínská 5 77900 Olomouc Czech Republic

Department of Organic Chemistry Faculty of Natural Science Charles University Hlavova 2030 12800 Prague 2 Czech Republic

Institute of Inorganic Chemistry of the Czech Academy of Sciences 250 68 Řež Czech Republic

Institute of Molecular and Translational Medicine Olomouc Hněvotínská 1333 5 77900 Olomouc Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Flemingovo nam 2 16610 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague Czech Republic

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