Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation

  • Eur J Med Chem. 2020 Apr 15;192:112156. doi: 10.1016/j.ejmech.2020.112156.
Qin Tang  1 ,  Weitao Fu  1 ,  Minkui Zhang  1 ,  Ercheng Wang  1 ,  Lvhu Shan  2 ,  Xin Chai  1 ,  Jinping Pang  1 ,  Xuwen Wang  1 ,  Xiaohong Xu  2 ,  Lei Xu  3 ,  Dan Li  4 ,  Rong Sheng  5 ,  Tingjun Hou  6
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
  • 2. Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China.
  • 3. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, Jiangsu, China.
  • 4. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address: [email protected].
  • 5. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address: [email protected].
  • 6. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address: [email protected].
PMID: 32114360 DOI: 10.1016/j.ejmech.2020.112156
Abstract

Androgen Receptor (AR) plays important roles in the development of prostate Cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate Cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 μM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.

Keywords
Androgen receptor; Antagonist; Molecular docking; Prostate cancer; Structure-based virtual screening.
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