2. Academic Validation
  3. Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation

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

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: lidancps@zju.edu.cn.
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address: shengrong1973@163.com.
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address: tingjunhou@zju.edu.cn.
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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