Fine structural design of 3βHSD1 inhibitors for prostate cancer
文献类型：期刊论文
| 作者 | He, Dongyin6; Zhang, Luyao4,5; Yu, Leiye2,3; Zhang, Yuhang6; Chen, Jingjing5; Wang, Leibo5; Hu, Haoran11; Liu, Hongyu7; Zheng, Hong4; Xia, Jixin6 |
| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
 |
| 出版日期 | 2025-07-01 |
| 卷号 | 122期号:26页码:12 |
| 关键词 | prostate cancer drug development AlphaFold molecular simulations 3 beta 3HSD1 |
| ISSN号 | 0027-8424 |
| DOI | 10.1073/pnas.242226712 |
| 英文摘要 | 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. |
| WOS关键词 | ANDROGEN-DEPRIVATION THERAPY ; ABIRATERONE ACETATE ; 3-BETA-HYDROXYSTEROID DEHYDROGENASE ; ANTITUMOR-ACTIVITY ; INCREASED SURVIVAL ; ENZALUTAMIDE ; HSD3B1 ; ANTIANDROGEN ; DOCETAXEL ; SOFTWARE |
| 资助项目 | National Key R&D Program of China[2023YFC3404700] ; Strategic Priority Research Program of the Chinese Academy of Science[XDB0570000] ; National Natural Science Foundation of China[82430090] ; National Natural Science Foundation of China[82441033] ; National Natural Science Foundation of China[32301003] ; National Natural Science Foundation of China[92157101] ; Natural Science Foundation of Shanghai[23ZR1469800] ; State Key Laboratory of Drug Research[SKLDR-2024-KF-03] ; Open Research Fund of State Key Laboratory of Genetic Engineering, Fudan University[SKLGE-2302] ; Lingang Laboratory Grant[LG-QS-202204-06] ; Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ-20210324124611031] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001526909500001 |
| 出版者 | NATL ACAD SCIENCES |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318828]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Liu, Jia; Ren, Ruobing; Hu, Youhong; Li, Zhenfei |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou 310024, Peoples R China 2.Shanghai Jiao Tong Univ, Dept Otolaryngol Head & Neck Surg, Shanghai Peoples Hosp 6, Sch Med, Shanghai 200233, Peoples R China 3.Fudan Univ, Shanghai Xuhui Cent Hosp, Zhongshan Xuhui Hosp, Inst Metab & Integrat Biol,Shanghai Key Lab Metab, Zhongshan 200437, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Beijing 110039, Peoples R China 5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 6.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci,Key Lab Multicell Syst, Shanghai 200031, Peoples R China 7.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Key Lab Tissue Microenvironm & Tumor, Shanghai 200031, Peoples R China 8.Chinese Univ Hong Kong, Sch Med, Shenzhen 518172, Guangdong, Peoples R China 9.Chinese Acad Sci, Dept Med Chem, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 10.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | He, Dongyin,Zhang, Luyao,Yu, Leiye,et al. Fine structural design of 3βHSD1 inhibitors for prostate cancer[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2025,122(26):12. |
| APA | He, Dongyin.,Zhang, Luyao.,Yu, Leiye.,Zhang, Yuhang.,Chen, Jingjing.,...&Li, Zhenfei.(2025).Fine structural design of 3βHSD1 inhibitors for prostate cancer.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122(26),12. |
| MLA | He, Dongyin,et al."Fine structural design of 3βHSD1 inhibitors for prostate cancer".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122.26(2025):12. |
入库方式： OAI收割
来源：上海药物研究所
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