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.

Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors

CATUCCI, GIANLUCA;OCCHIPINTI, Andrea;MAFFEI, Massimo Emilio;GILARDI, Gianfranco;SADEGHI, JILA
2013

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.
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http://dx.doi.org/10.3390/ijms14022707
flavin monoxygenases; drug metabolism; enzyme catalysis; kinase inhibitors
G. Catucci; A. Occhipinti; M. Maffei; G. Gilardi; S.J. Sadeghi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/127804
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