Faculty Collaboration Database

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo. J Med Chem 2022 Apr 28;65(8):6039-6055

Date

04/12/2022

Pubmed ID

35404047

Pubmed Central ID

PMC9059124

DOI

10.1021/acs.jmedchem.1c01878

Scopus ID

2-s2.0-85129087648 (requires institutional sign-in at Scopus site)   5 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-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.

Author List

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

Author

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Genetically Modified
Heterografts
Humans
Neuroblastoma
Receptors, Calcitriol
Vitamins