2025-06-26 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202507/t20250701_1046516.shtml
- https://www.pnas.org/doi/10.1073/pnas.2422267122
前立腺がん治療のための3βHSD1阻害剤の精密構造デザイン Fine structural design of 3βHSD1 inhibitors for prostate cancer therapy
Dongyin He, Luyao Zhang, Leiye Yu, +14 , and Zhenfei Li
Proceedings of the National Academy of Sciences Published:June 25, 2025
DOI:https://doi.org/10.1073/pnas.2422267122
Significance
The steroidogenic enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) correlates with tumor aggressiveness, and its inhibitors, biochanin-A (BCA) and the related analogs, have shown antitumor activities in various preclinical models and patients. However, the optimization of BCA for clinical use has been hindered by the lack of structural information on 3βHSD1. Here, we used advanced computational methods to conduct a structure-based compound design based on AlphaFold2 and developed a 3βHSD1 inhibitor, HEAL-116. HEAL-116 has better binding properties, improved oral absorption, and more potent antitumor effects in preclinical models. Our work demonstrates the feasibility of using predicted structural models for optimizing lead compound, and HEAL-116 provides a promising avenue for the clinical validation of 3βHSD1 inhibitors in prostate cancer therapy.
Abstract
Prostate cancer is a global health challenge, particularly for patients resistant to the second-generation anti-androgen receptor pathway inhibitors. The steroidogenic enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) 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 3βHSD1 inhibitors. AlphaFold2 was utilized to construct detailed models of 3βHSD1 binding to various substrates. These models, in conjunction with the elucidated enzymatic mechanism of 3βHSD1, guided the optimization of a series of BCA-related compounds. Our structure–activity relationship studies identified HEAL-116 as a potent 3βHSD1 inhibitor. HEAL-116 exhibited enhanced binding specificity to the substrate-binding pocket of 3βHSD1 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 3βHSD1 activity and exerted pronounced antitumor effect in biochemical, cellular, and mouse models. Our findings lay the foundation for the clinical translation of 3βHSD1 inhibitors, offering a promising therapeutic strategy for the management of prostate cancer and potentially other diseases.
