{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T03:46:48Z","timestamp":1788580008719,"version":"build-2803163510"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"\n Background<\/jats:title>\n \n Brain cancers are notorious for their heterogeneity, which complicates therapeutic decisions because of recurrently dysregulated signaling pathways. Cancer system characterizations have allowed the identification of some key components involved in brain cancer, such as the epidermal growth factor receptor,\n BRAF<\/jats:italic>\n , platelet-derived growth factor receptor alpha,\n TP53<\/jats:italic>\n , O6-methylguanine-DNA methyltransferase, cyclin-dependent kinase 1\/2\/3\/4, cyclooxygenase 1\/2, vascular endothelial growth factor receptor 2, telomerase reverse transcriptase, and CYP2D6, along with the U87 cell line. These components are the core focus of protocol designs for rational drug selection. For drug repurposing, these designed protocols are generally hypothesized with Food and Drug Administration (FDA)-approved drugs.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In the present study, a protocol was designed to address this complexity using the identified pathway components. These components served as the basis for defining the signatures of small molecules. The set of molecular signatures was then used to develop a network-driven computational framework. Accordingly, two in-house applications were developed, namely, a molecular profile generator called \u201c\n in-mac<\/jats:italic>\n \u201d and a network-based database called \u201cReBrain\u201d, derived from FDA-approved drug molecules.\n In-mac<\/jats:italic>\n is a computational bioassay platform that generates the activity profiles of small molecules, while ReBrain is a database used for broad-spectrum drug-repurposing analytics. The performance of the profile set was evaluated and validated using five machine-learning models with three different classified datasets.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 2,809 FDA-approved drug molecules (molecular weight \u2264500 Da) were profiled using\n in-mac<\/jats:italic>\n , and each molecular profile included fifteen-dimensional activity signatures. The profile set was then proven to have significant potential for drug repurposing. The molecular profiles were next used in a regression analysis, followed by the calculation of the intermolecular Euclidean distances and the development of an intermolecular network. The ReBrain platform also enabled\n in silico<\/jats:italic>\n knockout or knock-in capabilities for specific pathway components. Finally, network refinement was achieved using the molecular weights and distance thresholds.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The proposed profile-network-based method achieved 70%\u201395% accuracy for drug repurposing across different disease categories related to the brain.\n In-mac<\/jats:italic>\n and ReBrain were used for the repurposing of known drugs for the treatment of brain cancer. As a result, three repurposed drugs were identified as priorities: (i) mefloquine (reference drug: vorasidenib citrate), (ii) clofibric acid (reference drug: carmustine), and armillarisin A (reference drug: lomustine). These results also suggest repurposing candidates for synergistic combinations across different brain tumors. The two applications developed in this work are freely accessible and in the public domain at\n https:\/\/assay.smallmoles.com\/escorwin<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1768081","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T06:33:48Z","timestamp":1771310028000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A network-driven computational framework for identifying FDA-approved drug repurposing across heterogeneous brain cancers"],"prefix":"10.3389","volume":"13","author":[{"given":"Om","family":"Prakash","sequence":"first","affiliation":[{"name":"The Institute of Mathematical Sciences (IMSc)","place":["Chennai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"B1","first-page":"1","article-title":"Deep learning-driven drug development by identifying human protein targets","volume-title":"IEEE 9th international conference on engineering technologies and applied sciences (ICETAS)","author":"Balamurugan","year":""},{"key":"B2","first-page":"787","article-title":"Development of cancer drug targets and potential anti-cancer agents using deep learning and screening processes","volume-title":"5th international conference on data intelligence and cognitive informatics (ICDICI), Tirunelveli, India","author":"Balamurugan","year":""},{"key":"B3","first-page":"666","article-title":"Development of precision medicine for hepatic cancer evolving molecular profiling techniques through artificial intelligence","volume-title":"8th IET smart cities symposium (SCS 2024), hybrid conference","author":"Balamurugan","year":""},{"key":"B4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/1758-2946-5-24","article-title":"JSME: a free molecule editor in JavaScript","volume":"5","author":"Bienfait","year":"2013","journal-title":"J. Cheminform"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.3390\/ijms26052192","article-title":"A review of FDA-approved multi-target angiogenesis drugs for brain tumor therapy","volume":"26","author":"Buzatu","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1002\/pbc.20803","article-title":"MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma","volume":"48","author":"Donson","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"B7","doi-asserted-by":"publisher","first-page":"324","DOI":"10.3390\/biomedicines9030324","article-title":"Current FDA-approved therapies for high-grade malignant gliomas","volume":"9","author":"Fisher","year":"2021","journal-title":"Biomedicines"},{"key":"B8","first-page":"1","article-title":"Comprehensive in vivo and in vitro platform for evaluating drug efficacy against cancer cells in patient treatment","volume-title":"IEEE 9th international conference on engineering technologies and applied sciences (ICETAS)","author":"Gawri","year":"2024"},{"key":"B9","doi-asserted-by":"publisher","first-page":"637","DOI":"10.3390\/brainsci15060637","article-title":"Integrated workflow for drug repurposing in glioblastoma: computational prediction and preclinical validation of therapeutic candidates","volume":"15","author":"Gonzalez","year":"2025","journal-title":"Brain Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"107296","DOI":"10.1016\/j.ejps.2025.107296","article-title":"Repurposing of FDA-approved drugs by targeting SIRT2 to alleviate inflammatory response and kidney injury","volume":"214","author":"Huang","year":"2025","journal-title":"Eur. J. Pharm. Sci."},{"key":"B11","first-page":"481","article-title":"Intelligent drug release system development and evaluation via support vector machine algorithm","volume-title":"2024 international conference on innovation and intelligence for informatics, computing, and technologies (3ICT)","author":"Jayaraman","year":"2024"},{"key":"B12","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s12974-025-03455-x","article-title":"Repurposing of epalrestat for neuroprotection in Parkinson's disease via activation of the KEAP1\/Nrf2 pathway","volume":"22","author":"Jia","year":"2025","journal-title":"J. Neuroinflammation"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4689","DOI":"10.1007\/s00210-024-03625-3","article-title":"Harnessing network pharmacology in drug discovery: an integrated approach","volume":"398","author":"Joshi","year":"2025","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"6021","DOI":"10.1073\/pnas.1303607110","article-title":"TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal","volume":"110","author":"Killela","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"8518945","DOI":"10.1155\/2016\/8518945","article-title":"Biomolecular network-based synergistic drug combination discovery","volume":"2016","author":"Li","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"B16","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41392-022-01260-z","article-title":"Signaling pathways in brain tumors and therapeutic interventions","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"6946","DOI":"10.3390\/ijms25136946","article-title":"Repurposing anticancer drugs targeting the MAPK\/ERK signaling pathway for the treatment of respiratory virus infections","volume":"25","author":"Liu","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1093\/jac\/dkaf369","article-title":"A drug-repurposing screen of FDA- and EMA-approved drugs identifies two NF-\u03baB inhibitors active against eumycetoma","volume":"80","author":"Ma","year":"2025","journal-title":"J. Antimicrob. Chemother."},{"key":"B19","doi-asserted-by":"publisher","first-page":"11077","DOI":"10.1038\/s41467-025-67243-0","article-title":"Repurposing clinically safe drugs for DNA repair pathway choice in CRISPR genome editing and synthetic lethality","volume":"16","author":"Macak","year":"2025","journal-title":"Nat. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3705","DOI":"10.3390\/cancers14153705","article-title":"Drug repurposing, a fast-track approach to develop effective treatments for glioblastoma","volume":"14","author":"Ntafoulis","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"104679","DOI":"10.1016\/j.ijmedinf.2021.104679","article-title":"Potential applications and performance of machine learning techniques and algorithms in clinical practice: a systematic review","volume":"159","author":"Nwanosike","year":"2022","journal-title":"Int. J. Med. Inf."},{"key":"B22","doi-asserted-by":"publisher","first-page":"vdaa025","DOI":"10.1093\/noajnl\/vdaa025","article-title":"TERT, a promoter of CNS malignancies","volume":"2","author":"Patel","year":"2020","journal-title":"Neurooncol Adv."},{"key":"B23","doi-asserted-by":"publisher","first-page":"125935","DOI":"10.1016\/j.ijpharm.2025.125935","article-title":"Repurposing neurological drugs for brain cancer therapeutics: a systematic approach to identify charged molecules for affinity-based local drug delivery systems","volume":"682","author":"Sarker","year":"2025","journal-title":"Int. J. Pharm."},{"key":"B24","doi-asserted-by":"publisher","first-page":"116","DOI":"10.2174\/2589977514666220214120403","article-title":"Network-based drug repurposing: a critical review","volume":"14","author":"Selvaraj","year":"2022","journal-title":"Curr. Drug Res. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s00284-023-03304-1","article-title":"Repurposing of RAS-pathway mediated drugs for intestinal inflammation related diseases for treating SARS-CoV-2 infection","volume":"80","author":"Sinha","year":"2023","journal-title":"Curr. Microbiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"600","DOI":"10.3390\/genes16050600","article-title":"Signaling pathways in gliomas","volume":"16","author":"Stachyra","year":"2025","journal-title":"Genes (Basel)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4264","DOI":"10.3390\/cancers14174264","article-title":"BRAF and MEK targeted therapies in pediatric central nervous system tumors","volume":"14","author":"Talloa","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.bbrc.2021.09.069","article-title":"Mefloquine as a dual inhibitor of glioblastoma angiogenesis and glioblastoma via disrupting lysosomal function","volume":"580","author":"Wan","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.brainres.2010.08.075","article-title":"Chronic treatment with fibrates elevates superoxide dismutase in adult mouse brain microvessels","volume":"1359","author":"Wang","year":"2010","journal-title":"Brain Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0323597","DOI":"10.1371\/journal.pone.0323597","article-title":"Mechanistic role of pyroptosis in Kawasaki disease: an integrative bioinformatics analysis of immune dysregulation, machine learning-based biomarker discovery, WGCNA, and drug repurposing insights","volume":"20","author":"Wang","year":"2025","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2485","DOI":"10.1038\/s41598-023-28421-6","article-title":"Logistic regression technique is comparable to complex machine learning algorithms in predicting cognitive impairment related to post intensive care syndrome","volume":"13","author":"Wu","year":"2023","journal-title":"Sci. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41392-024-01808-1","article-title":"Drug repurposing for cancer therapy","volume":"9","author":"Xia","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.3389\/fonc.2019.01547","article-title":"O6-Methylguanine-DNA methyltransferase (MGMT): Challenges and new opportunities in glioma chemotherapy","volume":"9","author":"Yu","year":"2020","journal-title":"Front. Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1440922","DOI":"10.3389\/fimmu.2024.1440922","article-title":"Exploring the shared mechanism of fatigue between systemic lupus erythematosus and myalgic encephalomyelitis\/chronic fatigue syndrome: monocytic dysregulation and drug repurposing","volume":"15","author":"Zheng","year":"2025","journal-title":"Front. Immunol."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1768081\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T06:33:50Z","timestamp":1771310030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1768081\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":34,"alternative-id":["10.3389\/fmolb.2026.1768081"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1768081","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,17]]},"article-number":"1768081"}}