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, li...

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Published inJournal of medicinal chemistry Vol. 65; no. 8; pp. 6039 - 6055
Main Authors Khazan, Negar, Kim, Kyu Kwang, Hansen, Jeanne N., Singh, Niloy A., Moore, Taylor, Snyder, Cameron W. A., Pandita, Ravina, Strawderman, Myla, Fujihara, Michiko, Takamura, Yuta, Jian, Ye, Battaglia, Nicholas, Yano, Naohiro, Teramoto, Yuki, Arnold, Leggy A., Hopson, Russell, Kishor, Keshav, Nayak, Sneha, Ojha, Debasmita, Sharon, Ashoke, Ashton, John M., Wang, Jian, Milano, Michael T., Miyamoto, Hiroshi, Linehan, David C., Gerber, Scott A., Kawar, Nada, Singh, Ajay P., Tabdanov, Erdem D., Dokholyan, Nikolay, Kakuta, Hiroki, Jurutka, Peter W., Schor, Nina F., Rowswell-Turner, Rachael B., Singh, Rakesh K., Moore, Richard G.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 28.04.2022
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
D ANALOG
MODELS
MYC
1,25-DIHYDROXYVITAMIN-D3
COMPETITION BINDING ASSAY
NEUROBLASTOMA
CANCER
EXPRESSION
CALCITRIOL
INSIGHTS
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01878