Wilmot Cancer Institute and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester New York 14624, United States.
Department of Pediatrics, University of Rochester Medical Center, Rochester, New York 14642, United States.
J Med Chem. 2022 Apr 28;65(8):6039-6055. doi: 10.1021/acs.jmedchem.1c01878. Epub 2022 Apr 11.
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 (), which can be synthesized from 7-dehydrocholesterol () 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 . The VDR selectivity of against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 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.
维生素 D 受体 (VDR) mRNA 在神经母细胞瘤和肺癌、胰腺癌和卵巢癌中过表达，并预测预后不良。VDR 拮抗剂可能能够抑制过表达 VDR 的肿瘤。然而，目前的拮抗剂难以合成，且仅为部分拮抗剂，限制了它们的应用。在这里，我们展示了 VDR 拮抗剂 MeTC7 ()，它可以从 7-脱氢胆固醇 () 两步合成，选择性抑制 VDR，抑制癌细胞系的活力，并减少自发转基因 TH-MYCN 神经母细胞瘤和异种移植物的生长。对 RXRα 和 PPAR-γ 的 VDR 选择性进行了确认，并用 VDR-LBD 进行对接研究表明，诱导结合基序发生重大变化，这可能导致 VDR 拮抗作用。这些数据强调了针对 VDR 治疗恶性肿瘤的治疗益处，并证明了易于合成的选择性 VDR 拮抗剂的创建。
