{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:24:26Z","timestamp":1783513466196,"version":"3.55.0"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alliance of International Science Organisations for Young Talents Doctoral Fellowship","award":["2020A8017515005"],"award-info":[{"award-number":["2020A8017515005"]}]},{"name":"Science and Technology Planning Project of Guangdong Province, China","award":["2023B1212060050"],"award-info":[{"award-number":["2023B1212060050"]}]},{"name":"Science and Technology Planning Project of Guangdong Province, China","award":["2023B1212120009"],"award-info":[{"award-number":["2023B1212120009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: The dysregulation of the CDK1\/Cyclin B1 complex drives tumor progression in breast cancer (BC). The natural flavonoid luteolin (LT) shows anti-cancer potential, but its mechanism targeting CDK1\/CCNB1 remains unclear. Methods: CDK1, CCNB1, and CCNB2 expression were profiled in normal and BC cell lines. An engineered HEK293T GST-CDK1\/CCNB1 cell model was used to evaluate LT\u2019s effects on proliferation, ROS levels, and target gene transcription. Computational approaches (molecular docking, dynamics simulations, pharmacophore modeling, MM\/GBSA, ADMET, and network pharmacology) assessed LT and its analogues. Results: CDK1\/CCNB1 expression was lower in MCF7 BC cells than in normal cells, suggesting the loss of a growth barrier. In engineered HEK293T cells, LT suppressed CCNB1 transcription with minimal effect on CDK1 levels, correlating with anti-proliferative and ROS-modulating effects. Computational analyses confirmed stable LT binding to the CDK1\/CCNB1 complex. Designed LT analogues showed improved binding and favorable ADMET profiles. Network pharmacology identified cell cycle regulation, particularly in BC stem cells, as the primary pathway targeted. Conclusions: LT and its analogues inhibit the CDK1\/Cyclin B1 complex, revealing a dual mechanism that suppresses both tumor growth and BC stemness.<\/jats:p>","DOI":"10.3390\/ph19071048","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:19:31Z","timestamp":1783430371000},"page":"1048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Integrated Cellular Computational Pipeline Decodes Luteolin to Design Possible Allosteric CDK1\/CYCLIN B1 Inhibitors That Overcome Breast Cancer Stemness"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0128-8590","authenticated-orcid":false,"given":"Rajesh","family":"Basnet","sequence":"first","affiliation":[{"name":"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buddha Bahadur","family":"Basnet","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Nepal Academy of Science and Technology, Lalitpur 44700, Nepal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0954-4653","authenticated-orcid":false,"given":"Muhammad","family":"Majid","sequence":"additional","affiliation":[{"name":"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gogu Venkata Surendra","family":"Babu","sequence":"additional","affiliation":[{"name":"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7321-9121","authenticated-orcid":false,"given":"Obed Boadi","family":"Amissah","sequence":"additional","affiliation":[{"name":"Departments of Immunology, Physiology and Biomedical Engineering, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China"},{"name":"Department of Anatomy & Neurobiology, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s12032-022-01731-x","article-title":"Cyclin-dependent kinases in breast cancer: Expression pattern and therapeutic implications","volume":"39","author":"Sofi","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104806","DOI":"10.1016\/j.breast.2026.104791","article-title":"From CDK4\/6 to CDK2 and KAT: Evolving therapeutic approaches in HR+\/HER2\u2013breast cancer","volume":"88","author":"Stachyra","year":"2026","journal-title":"Breast"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zeng, H., Zhuang, M., Liang, B., Cai, F., Lin, M., Wang, R., Wang, R., and Zhang, H. (2025). CDK1 may promote breast cancer progression through AKT activation and immune modulation. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1591706"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1007\/s12282-020-01086-z","article-title":"Upregulated cyclins may be novel genes for triple-negative breast cancer based on bioinformatic analysis","volume":"27","author":"Lu","year":"2020","journal-title":"Breast Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2381714","DOI":"10.1080\/19476337.2024.2381714","article-title":"The potential role of luteolin, a flavonoid in cancer prevention and treatment","volume":"22","author":"Obaid","year":"2024","journal-title":"CyTA-J. Food"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Almatroodi, S.A., Almatroudi, A., Alharbi, H.O.A., Khan, A.A., and Rahmani, A.H. (2024). Effects and mechanisms of luteolin, a plant-based flavonoid, in the prevention of cancers via modulation of inflammation and cell signaling molecules. Molecules, 29.","DOI":"10.3390\/molecules29051093"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41392-024-02080-z","article-title":"Cyclin-dependent protein kinases and cell cycle regulation in biology and disease","volume":"10","author":"Pellarin","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e202409219","DOI":"10.1083\/jcb.202409219","article-title":"Plasticity of mitotic cyclins in promoting the G2\u2013M transition","volume":"224","author":"Crncec","year":"2025","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"\u00c7etinkaya, M., and Baran, Y. (2023). Therapeutic potential of luteolin on cancer. Vaccines, 11.","DOI":"10.3390\/vaccines11030554"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/0118715206406998251027105239","article-title":"Network Pharmacology Reveals Luteolin From Vitex Negundo Novel Targets CDK1\/Cyclin B In ER+ Breast Cancer Stem Cells","volume":"26","author":"Basnet","year":"2026","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.3390\/plants12112185","article-title":"Selection and validation of optimal RT-qPCR reference genes for the normalization of gene expression under different experimental conditions in Lindera megaphylla","volume":"12","author":"Liu","year":"2023","journal-title":"Plants"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1099\/0022-1317-36-1-59","article-title":"Characteristics of a human cell line transformed by DNA from human adenovirus type 5","volume":"36","author":"Graham","year":"1977","journal-title":"J. Gen. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Singh Tuli, H., Rath, P., Chauhan, A., Sak, K., Aggarwal, D., Choudhary, R., Sharma, U., Vashishth, K., Sharma, S., and Kumar, M. (2022). Luteolin, a Potent Anticancer Compound: From Chemistry to Cellular Interactions and Synergetic Perspectives. Cancers, 14.","DOI":"10.3390\/cancers14215373"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.2174\/138161210791164063","article-title":"Multi-targeted natural products evaluation based on biological activity prediction with PASS","volume":"16","author":"Lagunin","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhong, H.A. (2017). ADMET properties: Overview and current topics. Drug Design: Principles and Applications, Springer.","DOI":"10.1007\/978-981-10-5187-6_8"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bittermann, K., and Goss, K.-U. (2017). Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0190319"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s43556-024-00239-2","article-title":"Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer","volume":"6","author":"Gu","year":"2025","journal-title":"Mol. Biomed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.chembiol.2025.03.006","article-title":"CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers","volume":"32","author":"Kwiatkowski","year":"2025","journal-title":"Cell Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1038\/s41416-023-02468-8","article-title":"The Cyclin-dependent kinase 1: More than a cell cycle regulator","volume":"129","author":"Massacci","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3390\/ijms21061960","article-title":"The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer","volume":"21","author":"Ding","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25924","DOI":"10.1074\/jbc.M113.464669","article-title":"A chrysin derivative suppresses skin cancer growth by inhibiting cyclin-dependent kinases","volume":"288","author":"Liu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"220057","DOI":"10.1098\/rsob.220057","article-title":"Cell cycle-dependent binding between Cyclin B1 and Cdk1 revealed by time-resolved fluorescence correlation spectroscopy","volume":"12","author":"Barbiero","year":"2022","journal-title":"Open Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/s41429-021-00438-x","article-title":"Natural products targeting cancer cell dependency","volume":"74","author":"Shi","year":"2021","journal-title":"J. Antibiot."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/s41419-025-07533-z","article-title":"CARM1 S217 phosphorylation by CDK1 in late G2 phase facilitates mitotic entry","volume":"16","author":"Cho","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18184","DOI":"10.1038\/s41598-022-21364-4","article-title":"Proximal discrepancy in intrinsic atomic interaction arrests G2\/M phase by inhibiting Cyclin B1\/CDK1 to infer molecular and cellular biocompatibility of D-limonene","volume":"12","author":"Mandal","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Rakoczy, K., Kaczor, J., So\u0142tyk, A., Szyma\u0144ska, N., Stecko, J., Sleziak, J., Kulbacka, J., and Baczy\u0144ska, D. (2023). Application of luteolin in neoplasms and nonneoplastic diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115995"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1124\/mol.106.032185","article-title":"A Critical Role of Luteolin-Induced Reactive Oxygen Species in Blockage of Tumor Necrosis Factor-Activated Nuclear Factor-\u03baB Pathway and Sensitization of Apoptosis in Lung Cancer Cells","volume":"71","author":"Ju","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"829","DOI":"10.2174\/0115680096316247240715064729","article-title":"Network Pharmacology-based Virtual Screening of Chemical Constituents from Vitexnegundo Linn\u2019s Discovered Novel Molecular Targets for Breast Cancer Treatment","volume":"25","author":"Basnet","year":"2025","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tchurikov, N.A., Fedoseeva, D.M., Klushevskaya, E.S., Slovohotov, I.Y., Chechetkin, V.R., Kravatsky, Y.V., and Kretova, O.V. (2019). rDNA clusters make contact with genes that are involved in differentiation and cancer and change contacts after heat shock treatment. Cells, 8.","DOI":"10.3390\/cells8111393"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1186\/s13059-015-0768-0","article-title":"Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells","volume":"16","author":"Barutcu","year":"2015","journal-title":"Genome Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1158\/1055-9965.EPI-19-0066","article-title":"MCF-7 as a model for functional analysis of breast cancer risk variants","volume":"28","author":"Booms","year":"2019","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/nature23880","article-title":"Competing memories of mitogen and p53 signalling control cell-cycle entry","volume":"549","author":"Yang","year":"2017","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"116547","DOI":"10.1016\/j.ejmech.2024.116547","article-title":"Targeting cyclin-dependent kinases: From pocket specificity to drug selectivity","volume":"275","author":"Huang","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/s41375-022-01579-0","article-title":"Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia","volume":"36","author":"Stranahan","year":"2022","journal-title":"Leukemia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1039\/D2RA01375D","article-title":"Synthesis, biological and computational studies of flavonoid acetamide derivatives","volume":"12","author":"Isika","year":"2022","journal-title":"RSC Adv."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"de Aguiar, A.S.N., de Carvalho, L.B.R., Gomes, C.M., Castro, M.M., Martins, F.S., and Borges, L.L. (2025). Computational Insights into the Antioxidant Activity of Luteolin: Density Functional Theory Analysis and Docking in Cytochrome P450 17A1. Pharmaceuticals, 18.","DOI":"10.3390\/ph18030410"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1039\/D2CB00201A","article-title":"Emerging approaches to CDK inhibitor development, a structural perspective","volume":"4","author":"Hope","year":"2023","journal-title":"RSC Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10311","DOI":"10.1038\/s41598-025-94054-6","article-title":"Computational drug design for neurosyphilis disease by targeting Phosphoglycerate Kinase in Treponema pallidum with enhanced binding affinity and reduced toxicity","volume":"15","author":"Naveed","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/s10593-014-1496-1","article-title":"Prediction of the biological activity spectra of organic compounds using the PASS online web resource","volume":"50","author":"Filimonov","year":"2014","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1021\/ci300367a","article-title":"admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties","volume":"52","author":"Cheng","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties","volume":"49","author":"Xiong","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1048\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:08:20Z","timestamp":1783512500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1048"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071048"],"URL":"https:\/\/doi.org\/10.3390\/ph19071048","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]}}}