| 论文作者 |
He, DY; Zhang, LY; Yu, LY; Zhang, YH; Chen, JJ; Wang, LB; Hu, HR; Liu, HY; Zheng, H; Xia, JX; Chen, JH; Li, CH; Li, X; Tang, HR; Liu, J; Ren, RB; Hu, YH; Li, ZF |
| 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. |
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