MS05-P12 Structure-assisted design of Carborane inhibitors of human Carbonic Anhydrase IX Pavlina Rezacova (Institute of Organic Chemistry and Biochemistry, Czech Academy od Sciences, Prague, Czech Republic) Michael Kugler (Institute of Organic Chemistry and Biochemistry, Czech Academy od Sciences, Prague, Czech Republic) Jiri Brynda (Institute of Molecular Genetics, Czech Academy od Sciences, Prague, Czech Republic) Bohumir Gruner (Institute of Inorganic Chemistry, Czech Academy of Sciences, Rez, Czech Republic) Marián Hajduch (Institute of Molecular and Translational Medicine, Olomouc, Czech Republic) Jan Nekvinda (Institute of Inorganic Chemistry, Czech Academy of Sciences, Rez, Czech Republic) Klara Pospisilova (Institute of Organic Chemistry and Biochemistry, Czech Academy od Sciences, Prague, Czech Republic) Viswanath Das (Institute of Molecular and Translational Medicine, Olomouc, Czech Republic) Josef Holub (Institute of Inorganic Chemistry, Czech Academy of Sciences, Rez, Czech Republic)email: rezacova@img.cas.czCarbonic anhydrases (CAs) are zinc metalloenzymes playing an important role in many physiological processes. Several CAs are also involved in various pathological processes in humans and represent thus targets for drug development. Specifically, human carbonic Anhydrase IX (CA IX), isoform overexpressed in solid hypoxic tumours, is a target for cancer therapy and diagnostics. We have previously identified carboranes as a promising class of specific inhibitors of CA IX [1]. Here we report recent advances in the structure-assisted design of carborane and metallacarborane inhibitors targeting CA IX.
We chose carboranes, three-dimensional scaffolds, which act as as space-filling fragments. We modified boron cages to synthetize carboranes and metallacarboranes substituted by sulfamide, sulfonamide or sulfamate groups, i.e. functions known to bind tightly to the zinc atom in the active site of CAs. Consequently, the small library of ca. 70 substituted carboranes and metallacarboranes was. Several compounds exhibit selective inhibitory activity toward CAIX with  Ki values in low nanomolar or even picomolar range. Selected inhibitors were tested for their effect on tumor growth in BALB/c mice orthotopically implanted with 4T1 cells and SCID mice subcutaneous transplanted with HT-29 cells.

This work was supported by Czech Science Foundation, Project No. 15-05677S, Technology Agency of the Czech Republic, Projects No. TE01020028, and the Ministry of Education of the Czech Republic (LO1304 and EATRIS-CZ LM2015064 (programme “NPU I”).
 

 

References:

1. J. Brynda, P. Mader, V. Šícha, M. Fábry, K. Poncová, M. Bakardiev, B. Grüner, P. Cígler, P. Řezáčová, Angew Chem., Intl. Ed. Eng., 52, (2013), 13760.
Keywords: Anti-tumor agents, carborane inhibitors, Carbonic anhydrase IX