Unraveling the Efficacy of AR Antagonists Bearing N-(4-(Benzyloxy)phenyl)piperidine-1-sulfonamide Scaffold in Prostate Cancer Therapy by Targeting LBP Mutations

  • J Med Chem. 2025 Jun 12;68(11):11962-11978. doi: 10.1021/acs.jmedchem.5c00838.
Xin Chai  1 ,  Xinyue Wang  1 ,  Lvtao Cai  1 ,  Haiyi Chen  2 ,  Siyu Wang  1 ,  Jianing Liao  1 ,  Huating Wang  1 ,  Yuxin Zhou  1 ,  Lei Xu  3 ,  Luhu Shan  4 ,  Xiaohong Xu  4 ,  Yuhui Yang  5 ,  Junzhao He  5 ,  Yaqin Fu  5 ,  Tingjun Hou  1  6 ,  Rong Sheng  1  6 ,  Dan Li  1  6
Affiliations
  • 1. State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2. School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, Zhejiang, China.
  • 3. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, Jiangsu, China.
  • 4. 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.
  • 5. Key Laboratory of Advanced Textile Materials and Manufacturing Technology, Ministry of Education, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China.
  • 6. Jinhua Institute of Zhejiang University, Jinhua 321000, Zhejiang, China.
PMID: 40460055 DOI: 10.1021/acs.jmedchem.5c00838
Abstract

Point mutations in the Androgen Receptor (AR) are significant drivers of resistance in prostate Cancer (PCa), posing a great challenge to the development of effective treatment strategies. Building on our previous discovery of the suboptimal AR antagonist T1-12, we developed LT16, which contains an N-(4-(benzyloxy)phenyl)piperidine-1-sulfonamide scaffold through structural optimization and comprehensive screening against T878A-mutated AR. LT16 outperformed existing antiandrogens by fully antagonizing clinical AR mutations and effectively suppressing castration- and enzalutamide-resistant LNCaP cells proliferation in vitro. Mechanically, LT16 was found to disrupt AR nuclear translocation, hinder AR homodimerization, and suppress transcription of AR-regulated genes by competitive binding to the ligand binding pocket. Further in vivo experiments demonstrated that LT16 significantly reduced both regular- and enzalutamide-resistant LNCaP tumor volume and serum prostate-specific antigen levels in mice. These findings position LT16 as a promising and innovative therapeutic for advanced PCa, particularly in cases where resistance to current therapies is a concern.

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