2. Academic Validation
  3. Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

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. doi: 10.1021/acs.jmedchem.1c01878.
Negar Khazan 1,  Kyu Kwang Kim 1,  Jeanne N Hansen 2,  Niloy A Singh 1,  Taylor Moore 1,  Cameron W A Snyder 1,  Ravina Pandita 1,  Myla Strawderman 3,  Michiko Fujihara 4,  Yuta Takamura 4,  Ye Jian 5,  Nicholas Battaglia 5,  Naohiro Yano 6,  Yuki Teramoto 7,  Leggy A Arnold 8,  Russell Hopson 9,  Keshav Kishor 10,  Sneha Nayak 10,  Debasmita Ojha 10,  Ashoke Sharon 10,  John M Ashton 11,  Jian Wang 12,  Michael T Milano 13,  Hiroshi Miyamoto 7,  David C Linehan 5,  Scott A Gerber 5 13,  Nada Kawar 14,  Ajay P Singh 15,  Erdem D Tabdanov 16,  Nikolay V Dokholyan 12,  Hiroki Kakuta 4,  Peter W Jurutka 17 18,  Nina F Schor 19,  Rachael B Rowswell-Turner 1,  Rakesh K Singh 1,  Richard G Moore 1
Affiliations

Affiliations

  • 1 Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester New York 14624, United States.
  • 2 Department of Pediatrics, University of Rochester Medical Center, Rochester, New York 14642, United States.
  • 3 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York 14624, United States.
  • 4 Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8530, Japan.
  • 5 Division of Surgery and of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14624, United States.
  • 6 Department of Surgery, Division of Surgical Research, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island 02903, United States.
  • 7 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14624, United States.
  • 8 Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, Milwaukee, Wisconsin 53211, United States.
  • 9 Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States.
  • 10 Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
  • 11 Genomics Core Facility, Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14624, United States.
  • 12 Department of Pharmacology and Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State University, Hershey, Pennsylvania 17036, United States.
  • 13 Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York 16424, United States.
  • 14 Center for Breast Health and Gynecologic Oncology, Mercy Medical Center, 271 Carew Street, Springfield, Massachusetts 01104, United States.
  • 15 Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, New Jersey 08019, United States.
  • 16 CytoMechanobiology Laboratory, Department of Pharmacology, Penn State College of Medicine, Pennsylvania State University, Hershey, Pennsylvania 17036, United States.
  • 17 School of Mathematical and Natural Sciences, Arizona State University, Health Futures Center, Phoenix, Arizona 85054, United States.
  • 18 University of Arizona College of Medicine, Phoenix, Arizona 85004, United States.
  • 19 Departments of Pediatrics, Neurology, and Neuroscience, University of Rochester Medical Center, Rochester, New York 14642, United States.
PMID: 35404047 DOI: 10.1021/acs.jmedchem.1c01878
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147337
    98.52%, VDR Antagonist