{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:42:47Z","timestamp":1788950567707,"version":"build-2803163510"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"26","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"national key R&D program of China","doi-asserted-by":"crossref","award":["2023YFC3404700"],"award-info":[{"award-number":["2023YFC3404700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"national key R&D program of China","doi-asserted-by":"crossref","award":["2023YFC3402700"],"award-info":[{"award-number":["2023YFC3402700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:p>Prostate cancer is a global health challenge, particularly for patients resistant to the second-generation anti-androgen receptor pathway inhibitors. The steroidogenic enzyme 3\u03b2-hydroxysteroid dehydrogenase type 1 (3\u03b2HSD1) 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\u03b2HSD1 inhibitors. AlphaFold2 was utilized to construct detailed models of 3\u03b2HSD1 binding to various substrates. These models, in conjunction with the elucidated enzymatic mechanism of 3\u03b2HSD1, guided the optimization of a series of BCA-related compounds. Our structure\u2013activity relationship studies identified HEAL-116 as a potent 3\u03b2HSD1 inhibitor. HEAL-116 exhibited enhanced binding specificity to the substrate-binding pocket of 3\u03b2HSD1 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\u03b2HSD1 activity and exerted pronounced antitumor effect in biochemical, cellular, and mouse models. Our findings lay the foundation for the clinical translation of 3\u03b2HSD1 inhibitors, offering a promising therapeutic strategy for the management of prostate cancer and potentially other diseases.<\/jats:p>","DOI":"10.1073\/pnas.2422267122","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T11:38:07Z","timestamp":1750851487000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Fine structural design of 3\u03b2HSD1 inhibitors for prostate cancer therapy"],"prefix":"10.1073","volume":"122","author":[{"given":"Dongyin","family":"He","sequence":"first","affiliation":[{"name":"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","place":["Shanghai, 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Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]},{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery","place":["Yantai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-431X","authenticated-orcid":false,"given":"Zhenfei","family":"Li","sequence":"additional","affiliation":[{"name":"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","place":["Shanghai, China"]},{"name":"Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences","place":["Hangzhou, 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Hou S. Huang Z. Li Androgens in prostate cancer: A tale that never ends. Cancer Lett. 516 1\u201312 (2021).","DOI":"10.1016\/j.canlet.2021.04.010"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt138"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2013.06.042"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1586\/14737140.2014.949677"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.02394"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00148-1"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt136"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.07.029"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100608"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI171199"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30227-3"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.06.006"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0147"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.04.473"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.22967"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17954"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14406"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100561"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.77.9827"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clgc.2017.09.008"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clgc.2017.05.026"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0138"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.8807"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn6354"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2010.08.003"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0270077"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct700248k"},{"key":"e_1_3_4_36_2","unstructured":"D. He Data from \u201cFine structural design of 3\u03b2HSD1 inhibitors for prostate cancer therapy.\u201d National Omics Data Encyclopedia. https:\/\/www.biosino.org\/node\/browse?keyword=OEP005564. 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