The influence of belinostat inhibition on the activity of selected reductases from AKR and SDR superfamilies.

Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Adéla Slámová Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The influence of belinostat inhibition on the activity of selected reductases from AKR and SDR superfamilies Anthracycline antibiotics (ANTs) are important antineoplastic agents. One of them, daunorubicin (DAUN), is used for the treatment of acute leukaemia and other malignancies in children and adults. Factors limiting its clinical use include mainly resistance and cardiotoxicity. Enzymes from aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies mediated the reduction of DAUN to its C-13 alcohol metabolite daunorubicinol (DAUNOL). The metabolite is more cardiotoxic, less antineoplastic, and is causing anthracycline resistance. This diploma thesis aimed to examine the inhibitory effect of belinostat on the activity of AKR1A1, 1B1, 1B10, 1C3, and CBR1. The specific enzyme activity and inhibitory potential were estimated in vitro using recombinant enzymes, and the enzymatic production of DAUNOL was evaluated by the liquid chromatography (UHPLC) system. The inhibition was decreased in order AKR1C3 AKR1B10 AKR1A1 AKR1B1 CBR1. The most inhibited enzyme, AKR1C3, expressed 50,7%..