Using this approach, we have identified a number of pure inhibitors based on their high potency in inhibiting CYP24 activity and their low VDR transcriptional activity. The identified inhibitors (e.g., CTA091 IC50<10 nM; Figure 3) compared favorably to ketoconazole, which itself has a respectable IC50 in the 400–600 nM range. These inhibitors were selected because they exhibited low or no residual ability to induce CYP24 gene expression. In addition, inhibitors like CTA091 do not inhibit the closely related cytochrome P450s such as CYP27A (which metabolizes vitamin D3) or CYP27B1 (which metabolizes calcifediol).
Epidemiological studies have provided strong evidence that adequate endogenous supply of calcitriol is associated with reduced incidence of certain cancers including carcinomas of the prostate, colon, and breast.
Studies conducted both in vitro and in vivo support calcitriol’s role in regulating proliferation, differentiation, apoptosis, angiogenesis, and the metastatic processes involved in tumorigenesis.