Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors in Vivo

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; Richard G. Moore

doi:10.1021/acs.jmedchem.1c01878

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors in Vivo

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 SharonJohn 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, Richard G. Moore

Mathematical and Natural Sciences, School of (SMNS)

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	6039-6055
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	8
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01878
State	Published - Apr 28 2022

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c01878

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Khazan, N., Kim, K. K., Hansen, J. N., Singh, N. A., Moore, T., Snyder, C. W. A., Pandita, R., Strawderman, M., Fujihara, M., Takamura, Y., Jian, Y., Battaglia, N., Yano, N., Teramoto, Y., Arnold, L. A., Hopson, R., Kishor, K., Nayak, S., Ojha, D., ... Moore, R. G. (2022). 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. https://doi.org/10.1021/acs.jmedchem.1c01878

Khazan, N, Kim, KK, Hansen, JN, Singh, NA, Moore, T, Snyder, CWA, Pandita, R, Strawderman, M, Fujihara, M, Takamura, Y, Jian, Y, Battaglia, N, Yano, N, Teramoto, Y, Arnold, LA, Hopson, R, Kishor, K, Nayak, S, Ojha, D, Sharon, A, Ashton, JM, Wang, J, Milano, MT, Miyamoto, H, Linehan, DC, Gerber, SA, Kawar, N, Singh, AP, Tabdanov, ED, Dokholyan, NV, Kakuta, H, Jurutka, PW, Schor, NF, Rowswell-Turner, RB, Singh, RK & Moore, RG 2022, 'Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors in Vivo', Journal of Medicinal Chemistry, vol. 65, no. 8, pp. 6039-6055. https://doi.org/10.1021/acs.jmedchem.1c01878

@article{e302a36505144335a913c4a239785fcb,

title = "Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors in Vivo",

abstract = "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.",

author = "Negar Khazan and Kim, {Kyu Kwang} and Hansen, {Jeanne N.} and Singh, {Niloy A.} and Taylor Moore and Snyder, {Cameron W.A.} and Ravina Pandita and Myla Strawderman and Michiko Fujihara and Yuta Takamura and Ye Jian and Nicholas Battaglia and Naohiro Yano and Yuki Teramoto and Arnold, {Leggy A.} and Russell Hopson and Keshav Kishor and Sneha Nayak and Debasmita Ojha and Ashoke Sharon and Ashton, {John M.} and Jian Wang and Milano, {Michael T.} and Hiroshi Miyamoto and Linehan, {David C.} and Gerber, {Scott A.} and Nada Kawar and Singh, {Ajay P.} and Tabdanov, {Erdem D.} and Dokholyan, {Nikolay V.} and Hiroki Kakuta and Jurutka, {Peter W.} and Schor, {Nina F.} and Rowswell-Turner, {Rachael B.} and Singh, {Rakesh K.} and Moore, {Richard G.}",

year = "2022",

month = apr,

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doi = "10.1021/acs.jmedchem.1c01878",

language = "English (US)",

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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.

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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DO - 10.1021/acs.jmedchem.1c01878

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SN - 0022-2623

VL - 65

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EP - 6055

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors in Vivo

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