Fine structural design of 3βHSD1 inhibitors for prostate cancer

• 成果类型: Article
• 署名作者: He, Dongyin; Zhang, Luyao; Yu, Leiye; Zhang, Yuhang; Chen, Jingjing; Wang, Leibo; Hu, Haoran; Liu, Hongyu; Zheng, Hong; Xia, Jixin; Chen, Jiahui; Li, Chenhui; Li, Xin; Tang, Huiru; Liu, Jia; Ren, Ruobing; Hu, Youhong; Li, Zhenfei
• 署名单位: Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Fudan University; Shanghai Jiao Tong University; Fudan University; Chinese Academy of Sciences; Shanghai Institute of Nutrition & Health, CAS; University of Chinese Academy of Sciences, CAS; The Chinese University of Hong Kong, Shenzhen; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Shandong Laboratory of Yantai Drug Discovery; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9183
• DOI: 10.1073/pnas.242226712
• 发表日期: 2025-07-01
• 关键词: androgen-deprivation therapy; abiraterone acetate; 3-beta-hydroxysteroid dehydrogenase; antitumor-activity; increased survival; enzalutamide; hsd3b1; antiandrogen; docetaxel; software

摘要

Prostate cancer is a global health challenge, particularly for patients resistant to the second-generation anti-androgen receptor pathway inhibitors. The steroidogenic enzyme 3 beta-hydroxysteroid dehydrogenase type 1 (3 beta HSD1) has emerged as a promising therapeutic target and the corresponding inhibitors, biochanin-A (BCA) and its derivatives, suppress tumor growth in preclinical models and patients. However, the poor oral bioavailability of BCA hinders its clinical application. Here, we employed a sophisticated computational approach to refine the structural design of 3 beta HSD1 inhibitors. AlphaFold2 was utilized to construct detailed models of 3 beta HSD1 binding to various substrates. These models, in conjunction with the elucidated enzymatic mechanism of 3 beta HSD1, guided the optimization of a series of BCA-related compounds. Our structure-activity relationship studies identified HEAL-116 as a potent 3 beta HSD1 inhibitor. HEAL-116 exhibited enhanced binding specificity to the substrate-binding pocket of 3 beta HSD1 and effectively neutralized the local charge environment. The incorporation of hydrophilic groups in its structure also markedly enhanced its oral bioavailability. HEAL-116 robustly inhibited 3 beta HSD1 activity and exerted pronounced antitumor effect in biochemical, cellular, and mouse models. Our findings lay the foundation for the clinical translation of 3 beta HSD1 inhibitors, offering a promising therapeutic strategy for the management of prostate cancer and potentially other diseases.