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

International Journal of Molecular Sciences

Gianluca Catucci¹  Andrea Occhipinti¹  Massimo Maffei¹  Gianfranco Gilardi¹ 

[1] Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, Torino 10123, Italy;

关键词: phase I;    drug metabolism;    FMO3;    polymorphism;    enzyme kinetics;    VX-680;    PHA-739358;    LC-MS;   

DOI  :  10.3390/ijms14022707

来源: mdpi

【 摘 要 】

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 of Danusertib, V257M shows a 3.4× decrease in catalytic efficiency with k_cat/K_m 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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.