TY - JOUR
T1 - Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors in Vivo
AU - Khazan, Negar
AU - Kim, Kyu Kwang
AU - Hansen, Jeanne N.
AU - Singh, Niloy A.
AU - Moore, Taylor
AU - Snyder, Cameron W.A.
AU - Pandita, Ravina
AU - Strawderman, Myla
AU - Fujihara, Michiko
AU - Takamura, Yuta
AU - Jian, Ye
AU - Battaglia, Nicholas
AU - Yano, Naohiro
AU - Teramoto, Yuki
AU - Arnold, Leggy A.
AU - Hopson, Russell
AU - Kishor, Keshav
AU - Nayak, Sneha
AU - Ojha, Debasmita
AU - Sharon, Ashoke
AU - Ashton, John M.
AU - Wang, Jian
AU - Milano, Michael T.
AU - Miyamoto, Hiroshi
AU - Linehan, David C.
AU - Gerber, Scott A.
AU - Kawar, Nada
AU - Singh, Ajay P.
AU - Tabdanov, Erdem D.
AU - Dokholyan, Nikolay V.
AU - Kakuta, Hiroki
AU - Jurutka, Peter W.
AU - Schor, Nina F.
AU - Rowswell-Turner, Rachael B.
AU - Singh, Rakesh K.
AU - Moore, Richard G.
N1 - Funding Information:
The contents described in this report were partially supported by the University of Rochester CTSA award number UL1TR002001 from the National Center for Advancing Translational Sciences of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The contents described in this report were also supported partially by a Technology Development Fund (TDF) award to R.K.S., R.G.M., S.A.G., and D.L. and a Crosby’s Fund for Neuroblastoma Pediatric Cancer Research and the William H. Eilinger Endowment award to NFS. Data collected at the Colgate University by JNH (PI) was supported by a faculty discretionary grant for research supplies from the Colgate University Research Council. N.V.D. lists NIH (R35GM134864 and RF1AG071675), NSF (2040667), and Passan Foundation grant awards.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/28
Y1 - 2022/4/28
N2 - 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-γwas 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.
AB - 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-γwas 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.
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U2 - 10.1021/acs.jmedchem.1c01878
DO - 10.1021/acs.jmedchem.1c01878
M3 - Article
C2 - 35404047
AN - SCOPUS:85129087648
SN - 0022-2623
VL - 65
SP - 6039
EP - 6055
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 8
ER -
