Discovery of a Chalcone Compound Targeting Nur77 for the Treatment of Triple-Negative Breast Cancer

Discovery of a Chalcone Compound Targeting Nur77 for the Treatment of Triple-Negative Breast Cancer | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 25 February 2026 V1 Latest version Share on Discovery of a Chalcone Compound Targeting Nur77 for the Treatment of Triple-Negative Breast Cancer Authors : Beidou Zhou 0000-0001-8939-2386 [email protected] , Minda Zhang , Chun Lei , Yuexia Zhang , Ziyu Lin , Yizhen Chen , Chunqing Zhou , Siting Huang , Jieting Huang , and Jin-Zhang Zeng Authors Info & Affiliations https://doi.org/10.22541/au.177200138.89119230/v1 110 views 52 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Natural products and their synthetic derivatives remain vital to anticancer drug discovery. Chalcones represent a privileged scaffold due to their synthetic versatility and diverse bioactivities. We designed and synthesized a library of 24 chalcone compounds, evaluating their antitumor activity against five human cancer cell lines. Among these compounds, the trimethoxy-substituted analog, ( E )-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (Compound 22 ), emerged as the most potent lead compound, exhibiting nanomolar half-maximum inhibitory concentration (IC 50 ) values (0.028–0.075 µM) and outperforming cisplatin, particularly against triple-negative breast cancer (MDA-MB-231) cells. Mechanistic studies revealed a multi-targeted action. Network pharmacology implicated the PI3K/AKT pathway, identifying the orphan nuclear receptor Nur77 as a key target. Experimentally, compound 22 directly interacted with Nur77’s ligand-binding domain and upregulated its expression. Functionally, it inhibited cancer stem cell activity in 3D spheroids and induced significant tumor growth suppression in a murine MDA-MB-231 xenograft model, with confirmed Nur77 upregulation in vivo . These findings establish compound 22 as a highly promising lead compound that targets Nur77 and modulates the PI3K/AKT pathway, providing a strong rationale for its development as a therapeutic agent for aggressive cancers like triple-negative breast cancer. Supplementary Material File (manuscript_zbd_cjc.docx) Download 1.57 MB Information & Authors Information Version history V1 Version 1 25 February 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords anticancer activity chalcone nur77 pi3k/akt pathway structure-activity relationship (sar) triple-negative breast cancer (tnbc) Authors Affiliations Beidou Zhou 0000-0001-8939-2386 [email protected] Putian University Pharmaceutical and Medical Technology College View all articles by this author Minda Zhang Xiamen University School of Pharmaceutical Sciences View all articles by this author Chun Lei Putian University Pharmaceutical and Medical Technology College View all articles by this author Yuexia Zhang Putian University Pharmaceutical and Medical Technology College View all articles by this author Ziyu Lin Putian University Pharmaceutical and Medical Technology College View all articles by this author Yizhen Chen Putian University Pharmaceutical and Medical Technology College View all articles by this author Chunqing Zhou Putian University Pharmaceutical and Medical Technology College View all articles by this author Siting Huang Putian University Pharmaceutical and Medical Technology College View all articles by this author Jieting Huang Putian University Pharmaceutical and Medical Technology College View all articles by this author Jin-Zhang Zeng Xiamen University School of Pharmaceutical Sciences View all articles by this author Metrics & Citations Metrics Article Usage 110 views 52 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Beidou Zhou, Minda Zhang, Chun Lei, et al. Discovery of a Chalcone Compound Targeting Nur77 for the Treatment of Triple-Negative Breast Cancer. Authorea . 25 February 2026. DOI: https://doi.org/10.22541/au.177200138.89119230/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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