Multistep Binding of the Non-Steroidal Inhibitors Orteronel and Seviteronel to Human Cytochrome P450 17A1 and Relevance to Inhibition of Enzyme Activity

Orteronel (TAK-700)
is a substituted imidazole that was developed
for the treatment of castration-resistant prostate cancer but was
dropped in phase III clinical trials. Both enantiomers of this inhibitor
of cytochrome P450 (P450) 17A1 show some selectivity in differentially
blocking the 17α-hydroxylation and lyase activities of the enzyme.
Although both enantiomers of this compound have sub-micromolar IC50 values and bind to the enzyme with a type II spectral change
(indicative of nitrogen–iron bonding) and reported Kd values of 56 and 40 nM (R and S, respectively), the rates of binding to P450
17A1 were relatively slow. We considered the possibility that the
drug is a slow, tight-binding inhibitor. Analysis of the kinetics
of binding revealed rapid formation of an initial complex, presumably
in the substrate binding site, followed by a slower change to the
spectrum of a final iron complex. Similar kinetics were observed in
the interaction of another inhibitor, the triazole (S)-seviteronel (VT-464), with P450 17A1. Kinetic tests and modeling
indicate that the further change to the iron-complexed form of the
orteronel– or seviteronel–P450 complex is not a prerequisite
for enzyme inhibition. Accordingly, the inclusion of heme-binding
heterocyclic nitrogen moieties in P450 17A1 inhibitors may not be
necessary to achieve inhibition but may nevertheless augment the process.