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  3. Discovery of novel nonsteroidal VDR agonists with novel diarylmethane skeleton for the treatment of breast cancer

Discovery of novel nonsteroidal VDR agonists with novel diarylmethane skeleton for the treatment of breast cancer

  • Eur J Med Chem. 2019 Feb 1;163:787-803. doi: 10.1016/j.ejmech.2018.12.024.
Cong Wang 1,  Bin Wang 1,  Siyuan Hou 1,  Lingjing Xue 1,  Zisheng Kang 1,  Junjie Du 1,  Yanyi Li 1,  Xuwentai Liu 1,  Qianqian Wang 1,  Can Zhang 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
  • 2 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 30579121 DOI: 10.1016/j.ejmech.2018.12.024
Abstract

Vitamin D receptor (VDR) is recognized as a potential target for the treatment of breast Cancer which is the most common malignancy among women in the world. In this study, a series of nonsecosteroidal VDR agonists with a novel diarylmethane skeleton was designed, synthesized and the anti-tumor activities of these compounds were determined. Compound 28 was identified as the most effective agents in reducing the viability of MCF-7 cells, with a low IC50 via the inhibition of cell cycle and induction of Apoptosis by regulating the expression of p21, Bcl2 and Bax. In addition, compound 28 showed high VDR-binding affinity and displayed significant VDR-agonistic activities. Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators. In summary, these findings discovered novel VDR modulators as promising candidates for Cancer chemotherapy.

Keywords

Anti-Tumor activity; Breast cancer; Hypercalcemia; Nonsecosteroidal; Vitamin D receptor (VDR).

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