Discovery of N-(4-(Benzyloxy)-phenyl)-sulfonamide Derivatives as Novel Antagonists of the Human Androgen Receptor Targeting the Activation Function 2

  • J Med Chem. 2022 Feb 10;65(3):2507-2521. doi: 10.1021/acs.jmedchem.1c01938.
Xin Chai  1 ,  Huiyong Sun  2 ,  Wenfang Zhou  1 ,  Changwei Chen  3 ,  Luhu Shan  4 ,  Yuhui Yang  5 ,  Junzhao He  5 ,  Jinping Pang  1 ,  Liu Yang  1 ,  Xinyue Wang  1 ,  Sunliang Cui  3 ,  Yaqin Fu  5 ,  Xiaohong Xu  4 ,  Lei Xu  6 ,  Xiaojun Yao  7 ,  Dan Li  1 ,  Tingjun Hou  1  8
Affiliations
  • 1. Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
  • 3. Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, 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. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, Jiangsu, China.
  • 7. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China.
  • 8. State Key Lab of CAD&CG, Zhejiang University, Hangzhou 310058, Zhejiang, China.
PMID: 35077161 DOI: 10.1021/acs.jmedchem.1c01938
Abstract

Androgen Receptor (AR) antagonists have been widely used for the treatment of prostate Cancer (PCa). As a link between the AR and its transcriptional function, the activation function 2 (AF2) region has recently been revealed as a novel targeting site for developing AR antagonists. Here, we reported a series of N-(4-(benzyloxy)-phenyl)-sulfonamide derivatives as new-scaffold AR antagonists targeting the AR AF2. Therein, compound T1-12 showed excellent AR antagonistic activity (IC50 = 0.47 μM) and peptide displacement activity (IC50 = 18.05 μM). Furthermore, the in vivo LNCaP xenograft study confirmed that T1-12 offered effective inhibition on tumor growth when administered intratumorally. The study represents the first successful attempt to identify a small molecule targeting the AR AF2 with submicromolar AR antagonistic activity by structure-based virtual screening and provides important clues for the development of novel therapeutics for PCa treatment.

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