Identification of a Vitamin-D Receptor Antagonist, MeTC7, whichInhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuro-blastoma and carcinomas of lung, pancreas, and ovaries and predicts poorprognoses. VDR antagonists may be able to inhibit tumors that overexpressVDR. However, the current antagonists are arduous to synthesize and are onlypartial antagonists, limiting their use. Here, we show that the VDR antagonistMeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in twosteps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, andreduces the growth of the spontaneous transgenic TH-MYCN neuroblastomaand xenograftsin vivo. The VDR selectivity of5against RXR alpha and PPAR-gamma wasconfirmed, and docking studies using VDR-LBD indicated that5induces majorchanges in the binding motifs, which potentially result in VDR antagonisticeffects. These data highlight the therapeutic benefits of targeting VDR for thetreatment of malignancies and demonstrate the creation of selective VDRantagonists that are easy to synthesize.

Automated summary

This study investigates a novel VDR antagonist MeTC7 that selectively inhibits VDR, suppresses the viability of cancer cell-lines, and reduces the growth of neuroblastoma. The research findings contribute to the development of easy-to-synthesize selective VDR antagonists.