Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors.docVIP

Int. J. Mol. Sci. 2013, 14, 2707-2716; doi:10.3390/ijmOPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 /journal/ijms Article Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors Gianluca Catucci, Andrea Occhipinti, Massimo Maffei, Gianfranco Gilardi and Sheila J. Sadeghi * Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, Torino 10123, Italy; E-Mails: gianluca.catucci@unito.it (G.C.); andrea.occhipinti@unito.it (A.O.); massimo.maffei@unito.it (M.M.); gianfranco.gilardi@unito.it (G.G.) * Author to whom correspondence should be addressed; E-Mail: sheila.sadeghi@unito.it; Tel.: +39-011-670-4528; Fax: +39-011-670-4643. Received: 9 October 2012; in revised form: 22 December 2012 / Accepted: 18 January 2013 / Published: 28 January 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 k /K , similar to the wild-type: cat m ?1 ?1 ?1 ?1 0.39 ± 0.06 min μM for V257M compared to 0.33 ± 0.04 min μM for the wild type. On the other hand, in the case of Danusertib, V257M shows a 3.4× decrease in catalytic efficiency with k /K values of 0.05 ± 0.01 min μM?1 for V257M and ?1 cat m 0.17 ± 0.03 min μM?1 for the wild type. These