Abstract: Aurora kinases were recently identified as a potential target in anticancer therapy and, amongst their available inhibitors, Tozasertib (VX-680) and Danusertib (PHA-739358) have been indicated as possible substrates of human flavin-containing monooxygenase 3 (hFMO3). Here we report the in vitro rate of oxidation of these drugs by wild-type hFMO3 and its polymorphic variant V257M. The conversion of Tozasertib and Danusertib to their corresponding metabolites, identified by LC-MS, by the purified wild-type and V257M hFMO3 show significant differences. In the case of Tozasertib, the V257M variant shows a catalytic efficiency, expressed as kcat/Km, similar to the wild-type: 0.39 ± 0.06 min−1µM−1 for V257M compared to 0.33 ± 0.04 min−1µM−1 for the wild type. On the other hand, in the case of Danusertib, V257M shows a 3.4× decrease in catalytic efficiency with kcat/Km values of 0.05 ± 0.01 min−1µM−1 for V257M and 0.17 ± 0.03 min−1µM−1 for the wild type. These data reveal how a simple V257M substitution ascribed to a single nucleotide polymorphism affects the N-oxidation of relevant anticancer drugs, with important outcome in their therapeutic effects. These findings demonstrate that codon 257 is important for activity of the hFMO3 gene and the codon change V to M has an effect on the catalytic efficiency of this enzyme.
Keywords: phase I; drug metabolism; FMO3; polymorphism; enzyme kinetics; VX-680; PHA-739358; LC-MS
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Catucci, G.; Occhipinti, A.; Maffei, M.; Gilardi, G.; Sadeghi, S.J. Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors. Int. J. Mol. Sci. 2013, 14, 2707-2716.
Catucci G, Occhipinti A, Maffei M, Gilardi G, Sadeghi SJ. Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors. International Journal of Molecular Sciences. 2013; 14(2):2707-2716.
Catucci, Gianluca; Occhipinti, Andrea; Maffei, Massimo; Gilardi, Gianfranco; Sadeghi, Sheila J. 2013. "Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors." Int. J. Mol. Sci. 14, no. 2: 2707-2716.