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The absence of effective targeted therapies and endocrine treatment options leads to limited therapeutic options, which remains one of the major clinical challenges in TNBC management. Drug discovery is typically a lengthy and costly process that could be significantly improved through drug repurposing. However, the biological complexity and insufficient repurposing strategies hinder the reuse. This study aims to develop a deep learning-based framework to accelerate drug discovery for TNBC, identify novel therapeutic candidates, and uncover potential drug targets. We developed a deep neural network framework to predict the anticancer efficacy, toxicity profiles, and structural similarities of compounds. By applying this platform to screen over 6,000 compounds from the Drug Repurposing Hub, we identified promising candidates with potential therapeutic efficacy and safety profiles against TNBC. The top-predicted compounds were subsequently validated through comprehensive in vitro and in vivo functional assays. Furthermore, we employed transcriptomic sequencing and mass spectrometry-based proteomics to elucidate the molecular mechanisms underlying the anti-TNBC activity. We identified emodepside, a structurally unique molecule diverging from conventional anticancer agents that exhibited potent antitumor efficacy across multiple TNBC cell lines. Significantly, emodepside administration (5 mg\/kg) inhibited tumor growth in xenograft models. Integrated multiomics analyses (RNA-seq\/CETSA-MS) identified NAMPT as the primary target. This study demonstrates the viability of our deep learning models to discover structurally novel anticancer agents that are distinct from conventional drugs, thereby expanding the therapeutic arsenal for TNBC patients. Emodepside emerges as a promising TNBC therapeutic candidate, with a possible mechanism of promoting TNBC cell apoptosis via NAMPT inhibition.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01061","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:51:03Z","timestamp":1784771463000},"page":"8893-8907","source":"Crossref","is-referenced-by-count":0,"title":["Deep Learning-Driven\nAnticancer Drug Discovery: Emodepside\nas a Potential Therapeutic Candidate for Triple-Negative Breast Cancer"],"prefix":"10.1021","volume":"66","author":[{"given":"Yiyue","family":"Xu","sequence":"first","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences , , , ,","place":["Jinan, Shandong, China, 250117"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taotao","family":"Dong","sequence":"additional","affiliation":[{"name":"Qilu Hospital of Shandong University , , , ,","place":["Jinan, Shandong, China, 250012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Butuo","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences , , , ,","place":["Jinan, Shandong, China, 250117"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinming","family":"Yu","sequence":"additional","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences , , , ,","place":["Jinan, Shandong, China, 250117"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2231-6642","authenticated-orcid":true,"given":"Linlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong First Medical University and Shandong Academy of Medical Sciences , , , ,","place":["Jinan, Shandong, China, 250117"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"2026081008105845300_cit1","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3322\/caac.21863","article-title":"Breast cancer statistics\n2024","volume":"74","author":"Giaquinto","year":"2024","journal-title":"Ca-Cancer J. Clin."},{"key":"2026081008105845300_cit2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2022-071674","article-title":"Advances in systemic\ntherapies for triple negative\nbreast cancer","volume":"381","author":"Leon-Ferre","year":"2023","journal-title":"BMJ"},{"key":"2026081008105845300_cit3","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1158\/2159-8290.CD-18-1177","article-title":"Insights into\nMolecular Classifications\nof Triple-Negative Breast Cancer: Improving Patient Selection for\nTreatment","volume":"9","author":"Garrido-Castro","year":"2019","journal-title":"Cancer Discovery"},{"key":"2026081008105845300_cit4","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1200\/JCO.2009.25.6529","article-title":"American Society\nof Clinical Oncology\/College Of American Pathologists guideline recommendations\nfor immunohistochemical testing of estrogen and progesterone receptors\nin breast cancer","volume":"28","author":"Hammond","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"2026081008105845300_cit5","doi-asserted-by":"publisher","first-page":"3997","DOI":"10.1200\/JCO.2013.50.9984","article-title":"Recommendations\nfor human epidermal growth factor receptor 2 testing in breast cancer:\nAmerican Society of Clinical Oncology\/College of American Pathologists\nclinical practice guideline update","volume":"31","author":"Wolff","year":"2013","journal-title":"J. Clin.\nOncol."},{"key":"2026081008105845300_cit6","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","article-title":"Innovation in the pharmaceutical\nindustry: New estimates of R&D costs","volume":"47","author":"DiMasi","year":"2016","journal-title":"J.\nHealth Econ."},{"key":"2026081008105845300_cit7","doi-asserted-by":"publisher","DOI":"10.1001\/jamahealthforum.2023.0511","article-title":"Comparison\nof Research Spending on New Drug Approvals by the National Institutes\nof Health vs the Pharmaceutical Industry, 2010\u20132019","volume":"4","author":"Galkina Cleary","year":"2023","journal-title":"JAMA Health Forum"},{"key":"2026081008105845300_cit8","doi-asserted-by":"publisher","first-page":"5525","DOI":"10.1021\/jm401564r","article-title":"Discovery of innovative\ntherapeutics: today\u2019s\nrealities and tomorrow\u2019s vision. 2. Pharma\u2019s challenges\nand their commitment to innovation","volume":"57","author":"Abou-Gharbia","year":"2014","journal-title":"J. Med.\nChem."},{"key":"2026081008105845300_cit9","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/nbt.3052","article-title":"A community computational challenge\nto predict the activity of pairs of compounds","volume":"32","author":"Bansal","year":"2014","journal-title":"Nat. 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Res."},{"key":"2026081008105845300_cit26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009601","article-title":"Emodepside\ntargets SLO-1 channels\nof Onchocerca ochengi and induces broad anthelmintic effects in a\nbovine model of onchocerciasis","volume":"17","author":"Bah","year":"2021","journal-title":"PLoS Pathog."},{"key":"2026081008105845300_cit27","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1096\/fj.00-0664fje","article-title":"Latrophilin-like receptor from the parasitic nematode\nHaemonchus contortus as target for the anthelmintic depsipeptide PF1022A","volume":"15","author":"Saeger","year":"2001","journal-title":"FASEB J."},{"key":"2026081008105845300_cit28","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.ijpara.2012.05.009","article-title":"Decreased emodepside\nsensitivity in unc-49 \u03b3-aminobutyric acid (GABA)-receptor-deficient\nCaenorhabditis elegans","volume":"42","author":"Miltsch","year":"2012","journal-title":"Int. J. Parasitol."},{"key":"2026081008105845300_cit29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004062","article-title":"The Cyclooctadepsipeptide\nAnthelmintic\nEmodepside Differentially Modulates Nematode, Insect and Human Calcium-Activated\nPotassium (SLO) Channel Alpha Subunits","volume":"9","author":"Crisford","year":"2015","journal-title":"PLoS\nNegl. Trop. Dis."},{"key":"2026081008105845300_cit30","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s10158-012-0133-x","article-title":"Worms take to the slo lane: a perspective\non the mode of action of emodepside","volume":"12","author":"Holden-Dye","year":"2012","journal-title":"Invert.eber\nNeurosci."},{"key":"2026081008105845300_cit31","doi-asserted-by":"publisher","first-page":"2920","DOI":"10.1016\/j.bmcl.2016.04.039","article-title":"Application of virtual\nscreening to the discovery of novel nicotinamide phosphoribosyltransferase\n(NAMPT) inhibitors with potential for the treatment of cancer and\naxonopathies","volume":"26","author":"Clark","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081008105845300_cit32","doi-asserted-by":"publisher","first-page":"109516","DOI":"10.1016\/j.celrep.2021.109516","article-title":"NAD(+) supplement potentiates\ntumor-killing\nfunction by rescuing defective TUB-mediated NAMPT transcription in\ntumor-infiltrated T cells","volume":"36","author":"Wang","year":"2021","journal-title":"Cell Rep."},{"key":"2026081008105845300_cit33","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1158\/1078-0432.CCR-17-2575","article-title":"NAMPT Is a Potent Oncogene in Colon\nCancer Progression that Modulates Cancer Stem Cell Properties and\nResistance to Therapy through Sirt1 and PARP","volume":"24","author":"Lucena-Cacace","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"2026081008105845300_cit34","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1158\/0008-5472.CAN-19-2830","article-title":"NAMPT Inhibition\nSuppresses Cancer Stem-like Cells Associated with Therapy-Induced\nSenescence in Ovarian Cancer","volume":"80","author":"Nacarelli","year":"2020","journal-title":"Cancer Res."},{"key":"2026081008105845300_cit35","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.1158\/0008-5472.CAN-18-3418","article-title":"Epigenetic Regulation of NAMPT by\nNAMPT-AS Drives Metastatic Progression\nin Triple-Negative Breast Cancer","volume":"79","author":"Zhang","year":"2019","journal-title":"Cancer Res."},{"key":"2026081008105845300_cit36","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1002\/emmm.201201250","article-title":"Synthetic\nlethality of PARP and NAMPT\ninhibition in triple-negative breast cancer cells","volume":"4","author":"Bajrami","year":"2012","journal-title":"EMBO Mol. Med."},{"issue":"1","key":"2026081008105845300_cit37","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41392-020-00354-w","article-title":"NAD(+) metabolism, stemness, the immune response, and\ncancer","volume":"6","author":"Navas","year":"2021","journal-title":"Signal Transduction Targeted Ther."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c01061","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/15\/8893\/66174275\/acs.jcim.6c01061.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/15\/8893\/66174275\/acs.jcim.6c01061.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:25:28Z","timestamp":1786364728000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/15\/8893\/5228510\/Deep-Learning-Driven-Anticancer-Drug-Discovery"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":37,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,7,22]]},"published-print":{"date-parts":[[2026,8,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c01061","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]}}}