The enzymology of the selective CYP17 lyase inhibitor, VT-464, and its effects in castration-resistant prostate cancer (CRPC) models.
2014
158 Background: CRPC typically responds to anti-androgen therapy but resistance is common. CYP17 inhibitors that block lyase (L) and not hydroxylase (H), do not require prednisone, and may delay tumor resistance are needed. VT-464 is an oral, non-steroidal inhibitor of CYP17 L in clinical development for CRPC. The present studies characterized: 1) the kinetic mechanism of VT-464 inhibition of h-CYP17 L and H, and 2) VT-464 effects compared to abiraterone acetate (AA) in CRPC models. Methods: CYP17 Enzyme Assays: r-h-CYP17 inhibition studies were conducted using substrates pregnenolone (for H) or 17-a-hydroxypregnenolone (for L). Product rates (17-a-hydroxypregnenolone (H) and DHEA (L)) were assessed by LC/MS/MS. Data were fit to inhibition models using SigmaPlot 11.2. In vitro CRPC studies: VT-464 and AA effects on AR transcription (luciferase) and PSA and NKX3.1 gene expression (QRT-PCR) were compared in C4-2B cells. Mouse xenograft model: Effects of oral VT-464 or AA on tumor growth and tumoral steroids...
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