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Rational drug design for androgen receptor and glucocorticoids receptor dual antagonist

Meng Wu1, Yongli Xie1, Xiangling Cui1

  • 1Key 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.

European Journal of Medicinal Chemistry
|February 4, 2019
PubMed

Insights

Researchers developed Z19, a dual antagonist targeting both androgen receptor (AR) and glucocorticoid receptor (GR). This novel compound shows potential in overcoming resistance to prostate cancer therapies, offering a new treatment strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Drug Discovery

Background:

  • Prostate cancer (PCa) is a leading cause of cancer mortality in men.
  • Enzalutamide (ENZa), a second-generation antiandrogen, improves survival in metastatic castration-resistant prostate cancer (mCRPC).
  • Glucocorticoid receptor (GR) overexpression in mCRPC leads to resistance against antiandrogen therapy and AR-targeting treatments.

Purpose of the Study:

  • To develop a dual antagonist targeting both the androgen receptor (AR) and glucocorticoid receptor (GR).
  • To identify novel therapeutic agents for prostate cancer by addressing antiandrogen resistance mechanisms.

Main Methods:

  • Utilized virtual screening and biological evaluation based on antiandrogen chemical structures and GR crystal structure.
  • Identified and characterized Z19 as a dual AR/GR antagonist.

Main Results:

  • Z19 effectively inhibited the transcriptional activity of both AR and GR.
  • Z19 reduced the protein and mRNA levels of downstream signaling molecules regulated by GR and AR.
  • Z19 demonstrated potential as a lead compound for novel prostate cancer treatments.

Conclusions:

  • Rational drug design is an effective strategy for developing dual AR/GR antagonists.
  • Z19 represents a promising candidate for overcoming therapeutic resistance in prostate cancer.
  • Targeting both AR and GR offers a potential new avenue for mCRPC treatment.
Keywords:
Androgen receptorAntagonistEnzalutamide resistanceGlucocorticoids receptorProstate cancer

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