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
Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Proc Natl Acad Sci U S A. 2025 Jul;122(26):e2422267122. doi: 10.1073/pnas.2422267122. Epub 2025 Jun 25.
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.
前列腺癌是一项全球性的健康挑战，对于那些对第二代抗雄激素受体途径抑制剂耐药的患者而言尤其如此。类固醇生成酶1型3β-羟基类固醇脱氢酶（3βHSD1）已成为一个有前景的治疗靶点，其相应的抑制剂——染料木黄酮（BCA）及其衍生物，在临床前模型和患者中可抑制肿瘤生长。然而，BCA较差的口服生物利用度阻碍了其临床应用。在此，我们采用了一种精密的计算方法来优化3βHSD1抑制剂的结构设计。利用AlphaFold2构建了3βHSD1与各种底物结合的详细模型。这些模型，结合已阐明的3βHSD1酶促机制，指导了一系列与BCA相关化合物的优化。我们的构效关系研究确定HEAL-116为一种有效的3βHSD1抑制剂。HEAL-116对3βHSD1的底物结合口袋表现出增强的结合特异性，并有效中和了局部电荷环境。其结构中亲水性基团的引入也显著提高了其口服生物利用度。HEAL-116强烈抑制3βHSD1活性，并在生化、细胞和小鼠模型中发挥显著的抗肿瘤作用。我们的研究结果为3βHSD1抑制剂的临床转化奠定了基础，为前列腺癌及其他潜在疾病的治疗提供了一种有前景的治疗策略。
