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

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(cat)/K(m), 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

SUBMITTER: Catucci G 

PROVIDER: S-EPMC3588010 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature