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

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

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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