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

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Discovery of N-(4-(Benzyloxy)-phenyl)-sulfonamide Derivatives as Novel Antagonists of the Human Androgen Receptor Targeting the Activation Function 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-25 , 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,

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Affiliation

Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
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.
Key Laboratory of Advanced Textile Materials and Manufacturing Technology Ministry of Education, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China.
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, Jiangsu, China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China.
State Key Lab of CAD&CG, Zhejiang University, Hangzhou 310058, Zhejiang, China.

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.

中文翻译：

发现 N-(4-(苄氧基)-苯基)-磺酰胺衍生物作为针对激活功能的人类雄激素受体的新型拮抗剂 2

雄激素受体（AR）拮抗剂已广泛用于治疗前列腺癌（PCa）。作为 AR 及其转录功能之间的联系，激活功能 2 (AF2) 区域最近被揭示为开发 AR 拮抗剂的新靶点。在这里，我们报道了一系列N- (4-(苄氧基)-苯基)-磺酰胺衍生物作为针对 AR AF2 的新支架 AR 拮抗剂。其中，化合物T1-12表现出优异的AR拮抗活性(IC ₅₀ = 0.47 μM)和肽置换活性(IC ₅₀ = 18.05 μM)。此外，体内 LNCaP 异种移植研究证实，T1-12 瘤内给药时可有效抑制肿瘤生长。该研究代表了通过基于结构的虚拟筛选鉴定具有亚微摩尔AR拮抗活性的针对AR AF2的小分子的首次成功尝试，并为开发PCa治疗的新型疗法提供了重要线索。

更新日期：2022-02-10

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