2. Academic Validation
  3. Discovery of 5-Nitro- N-(3-(trifluoromethyl)phenyl) Pyridin-2-amine as a Novel Pure Androgen Receptor Antagonist against Antiandrogen Resistance

Discovery of 5-Nitro- N-(3-(trifluoromethyl)phenyl) Pyridin-2-amine as a Novel Pure Androgen Receptor Antagonist against Antiandrogen Resistance

  • J Med Chem. 2024 Nov 7. doi: 10.1021/acs.jmedchem.4c01970.
Huating Wang 1,  Xuwen Wang 1,  Haiyang Zhong 2,  Lvtao Cai 1,  Weitao Fu 3,  Xin Chai 1,  Jianing Liao 1,  Rong Sheng 1 4,  Luhu Shan 5,  Xiaohong Xu 5,  Lei Xu 6,  Peichen Pan 1,  Tingjun Hou 1,  Dan Li 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
  • 3 Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, Anhui, China.
  • 4 Jinhua Institute of Zhejiang University, Jinhua 321000, Zhejiang, China.
  • 5 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.
  • 6 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, Jiangsu, China.
PMID: 39508817 DOI: 10.1021/acs.jmedchem.4c01970
Abstract

The transformation of clinical Androgen Receptor (AR) antagonists into agonists driven by AR mutations poses a significant challenge in treating prostate Cancer (PCa). Novel anti-AR therapeutics combating mutation-induced resistance are required. Herein, by combining structure-based virtual screening and biological evaluation, a high-affinity agonist E10 was first discovered. Then guided by the representative conformation of State 1 at the free energy landscape, the structural optimization of E10 was performed, and pure AR antagonists EL15 (IC50 = 0.94 μM) and EF2 (IC50 = 0.30 μM) were successfully identified. Both can antagonize wild-type and variant drug-resistant ARs. Therein, EF2 demonstrated potent inhibition of the AR pathway and effectively suppressed tumor growth in a C4-2B xenograft mouse model following oral administration. Further molecular dynamics simulation and mutagenesis studies revealed atomic insights into the mode of action of EF2 which may serve as a novel lead compound for developing therapeutics against AR-driven PCa.

Figures
Products