Eva Novotna
Charles University, Czech Republic
Title: Dinaciclib effectively inhibits AKR1C3, a promising therapeutic target for cancer treatment
Biography
Biography: Eva Novotna
Abstract
Dinaciclib (MK-7965, SCH727965) is a cyclin-dependent kinase inhibitor. Dinaciclib recently enters Phase III clinical trial for the treatment of leukaemia. The results of the study shows its promising anti-leukemia activity and a tolerability. Dinaciclib causes apoptosis to several cancer cell lines, including those that are resistant to anthracyclines. The reductive metabolism of anthracyclines to their secondary C13-hydroxy metabolites is one of the main mechanisms leading to cancer resistance. To date, this kind of metabolism has been associated with members of the short-chain dehydrogenase/reductase (SDR) and of aldo-keto reductase superfamilies (AKR). In our study, dinaciclib was identified as an effective inhibitor of aldo-keto reductase 1C3 (AKR1C3), the enzyme that is overexpressed in many cancer types and its increased metabolism contributes to the pharmacokinetic resistance to antracyclines in tumor tissues. In our study, dinaciclib inhibited AKR1C3 in the experiments with purified recombinant enzyme (IC50=220 nM, Ki=170 nM) and was equally active at the cellular level (IC50=235 nM). Molecular docking studies predicted that dinaciclib occupies a part of the cofactor binding site, which is consistent with the noncompetitive mechanism of inhibition determined in our in vitro experiments. Furthermore, we demonstrated that pretreatment with dinaciclib significantly sensitized AKR1C3-overexpressing anthracycline-resistant cancer cells to daunorubicin. Our results indicate that dinaciclib may potentially increase the therapeutic efficacy of anthracyclines, prevent anthracycline resistance and minimize their adverse effects.