TABLE 1

In vitro evaluation of oprozomib as an inhibitor of six human P450 enzymes

Results representing the average data (i.e., percentage of control activity) obtained from duplicate samples from each test article concentration were used to calculate the IC50 values. The IC50 values were calculated using GraphPad Prism (version 6). The highest concentration of oprozomib tested in the assays was 30 µM.

EnzymeP450 ReactionInhibition of Human P450s by Oprozomib
Direct (0-Minute Preincubation)Time Dependent (30-Minute Preincubation)
IC50Inhibition at 30 µMaIC50Inhibition at 30 µMa
µM%µM%
CYP1A2Phenacetin O-deethylation>3021>30NAb
CYP2C8Amodiaquine N-dealkylation>3020>3013
CYP2C9Diclofenac 4′-hydroxylation>306.3>3024
CYP2C19S-Mephenytoin 4′-hydroxylation>3016>307.2
CYP2D6Dextromethorphan O-demethylation>300.2>303.7
CYP3A4/5Testosterone 6β-hydroxylation>30455.589
CYP3A4/5Midazolam 1′-hydroxylation>30331268
  • NA, not applicable.

  • a The inhibition (%) was calculated using the data for the highest concentration of test article evaluated and the following formula: inhibition (%) = 100% − % activity remaining of solvent control.

  • b No value was obtained since the rates at the highest concentration of oprozomib evaluated (30 µM) were higher than the control rates.