The influence of midostaurin, vistusertib and talazoparib 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. Jaroslav Milan Supervisor: prof. Ing. Vladimír Wsól, PhD. Consultant: RNDr. Eva Novotná, PhD. Title of diploma thesis: The influence of midostaurin, vistusertib and talazoparib inhibition on the activity of selected reductases from AKR and SDR superfamilies. Key words: reductase, AKR, inhibitors, midostaurin, vistusertib, talazoparib, anthracyclines, KG1a Multi drug resistance is for a lot of years still a big problem in therapy of cancer. Anthracycline antibiotics are highly efficient for treating cancers but multi drug resistance and severe side effects sometimes restrain the use of them and lead therapy to fail. One of the worst adverse effect is a cardiotoxicity. By older studies, the mechanism of a cardiotoxicity was because of formation of reactive oxygen species (ROS). Many times, the negative effects of ROS on cardiac muscle cells was confirmed but nowadays the evidence opens some other and more complex mechanisms of its damage. The main point of this work was examination of enzymes which metabolize anthracyclines, mainly daunorubicin. Metabolites which are formed are less potent than parent drug and they have bigger toxicity. This can have an impact on therapy and can cause a..