2. Academic Validation
  3. Rational drug design for androgen receptor and glucocorticoids receptor dual antagonist

Rational drug design for androgen receptor and glucocorticoids receptor dual antagonist

  • Eur J Med Chem. 2019 Mar 15:166:232-242. doi: 10.1016/j.ejmech.2019.01.036.
Meng Wu 1,  Yongli Xie 1,  Xiangling Cui 1,  Chenchao Huang 2,  Rongyu Zhang 2,  Yang He 3,  Xiaoyu Li 3,  Mingliang Liu 3,  Shan Cen 4,  Jinming Zhou 5
Affiliations

Affiliations

  • 1 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • 2 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: shancen@imb.pumc.edu.cn.
  • 5 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, PR China. Electronic address: zhoujinming@zjnu.edu.cn.
PMID: 30711833 DOI: 10.1016/j.ejmech.2019.01.036
Abstract

Prostate Cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male Cancer mortality in the western countries. The second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC. However, the overexpression of glucocorticoids receptor (GR) in mCRPC cells causes the resistance of antiandrogen and leads to the failure of Androgen Receptor (AR) targeting therapy. Herein, based on the chemical structures of antiandrogen and crystal structure of GR, we set up to develop GR/AR (GR and AR) dual antagonist by virtual screening and biological evaluation. We identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream proteins of GR and AR signaling, and provided a potential lead compound for the development of novel treatment agents of prostate Cancer. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate Cancer.

Keywords

Androgen receptor; Antagonist; Enzalutamide resistance; Glucocorticoids receptor; Prostate cancer.

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