Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize.
Negar Khazan, Kyu Kwang Kim, Jeanne N. Hansen, Niloy A. Singh, Taylor Moore, Cameron W. A. Snyder, Ravina Pandita, Myla Strawderman, Michiko Fujihara, Yuta Takamura, Ye Jian, Nicholas Battaglia, Naohiro Yano, Yuki Teramoto, Leggy A. Arnold, Russell Hopson, Keshav Kishor, Sneha Nayak, Debasmita Ojha, Ashoke Sharon, John M. Ashton, Jian Wang, Michael T. Milano, Hiroshi Miyamoto, David C. Linehan, Scott A. Gerber, Nada Kawar, Ajay P. Singh, Erdem D. Tabdanov*, Nikolay V. Dokholyan, Hiroki Kakuta*, Peter W. Jurutka, Nina F. Schor*, Rachael B. Rowswell-Turner, Rakesh K. Singh*, and Richard G. Moore. Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo. Journal of medicinal chemistry, 65(8), 6039-6055.