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

• Published in: Journal of medicinal chemistry Vol. 65; no. 3; pp. 2507 - 2521
• Main Authors: Chai, Xin, Sun, Huiyong, Zhou, Wenfang, Chen, Changwei, Shan, Luhu, Yang, Yuhui, He, Junzhao, Pang, Jinping, Yang, Liu, Wang, Xinyue, Cui, Sunliang, Fu, Yaqin, Xu, Xiaohong, Xu, Lei, Yao, Xiaojun, Li, Dan, Hou, Tingjun
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.02.2022
• Subjects: Androgen Receptor Antagonists - chemical synthesis; Androgen Receptor Antagonists - metabolism; Androgen Receptor Antagonists - therapeutic use; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Binding Sites; Cell Proliferation - drug effects; Gene Expression - drug effects; Humans; Male; Mice; Mice, SCID; Molecular Docking Simulation; Molecular Structure; Prostatic Neoplasms - drug therapy; Protein Transport - drug effects; Receptors, Androgen - chemistry; Receptors, Androgen - metabolism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - metabolism; Sulfonamides - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01938

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.