{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:28:17Z","timestamp":1787794097804,"version":"build-2784847793"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Dysregulation of the cyclin D\/CDK complex is a common feature in various cancers, including colorectal, breast, and melanoma, leading to uncontrolled tumor growth and cell cycle progression. Targeting this complex has become a compelling therapeutic approach in oncology. FDA-approved CDK4\/6 inhibitors, such as ribociclib, palbociclib, and abemaciclib, have demonstrated clinical efficacy, significantly improving patient outcomes. However, the development of resistance to these therapies emphasizes the urgent need for alternative strategies to overcome therapeutic limitations. The current study explores the potential of new inhibitors targeting the cyclin D\/CDK axis by using virtual screening and molecular dynamics simulations. We conducted a virtual screening of the Zinc and PubChem databases, by utilizing a pharmacophore model generated by PocketQuery, to identify new candidate inhibitors of the cyclin D\/CDK4 complex. The findings offer promising leads for further optimization, potentially paving the way for developing more effective treatments that circumvent resistance mechanisms and expand therapeutic options for cancer patients. Further experimental validation and in vivo studies are necessary to confirm the efficacy of these candidates and translate them into viable clinical treatments.<\/jats:p>","DOI":"10.1371\/journal.pone.0330102","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T17:34:23Z","timestamp":1755884063000},"page":"e0330102","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the cyclin D\/CDK4 Axis to unlock new therapeutic approaches to enhance cancer treatment"],"prefix":"10.1371","volume":"20","author":[{"given":"Ibrahim","family":"Khater","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5542-9387","authenticated-orcid":true,"given":"Aaya","family":"Nassar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"issue":"1","key":"pone.0330102.ref001","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0185637","article-title":"Cyclin D\/CDK4\/6 activity controls G1 length in mammalian cells","volume":"13","author":"P Dong","year":"2018","journal-title":"PLoS One"},{"issue":"3","key":"pone.0330102.ref002","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrc2602","article-title":"Cell cycle, CDKs and cancer: a changing paradigm","volume":"9","author":"M Malumbres","year":"2009","journal-title":"Nat Rev Cancer"},{"issue":"9","key":"pone.0330102.ref003","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nrm2469","article-title":"Conserved functions of the pRB and E2F families","volume":"9","author":"S van den Heuvel","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"pone.0330102.ref004","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0092-8674(03)01080-8","article-title":"Recycling the Cell Cycle","volume":"116","author":"AW Murray","year":"2004","journal-title":"Cell"},{"key":"pone.0330102.ref005","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.02872","article-title":"Cyclin D activates the Rb tumor suppressor by mono-phosphorylation","volume":"3","author":"AM Narasimha","year":"2014","journal-title":"eLife"},{"issue":"12","key":"pone.0330102.ref006","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1111\/febs.15586","article-title":"The multifaceted role of cell cycle regulators in the coordination of growth and metabolism","volume":"288","author":"K Huber","year":"2021","journal-title":"FEBS J"},{"key":"pone.0330102.ref007","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/bs.acr.2020.02.002","article-title":"Cyclin D-CDK4\/6 functions in cancer","volume":"148","author":"X Gao","year":"2020","journal-title":"Adv Cancer Res"},{"issue":"1","key":"pone.0330102.ref008","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1158\/1078-0432.CCR-18-1999","article-title":"To Cycle or Fight-CDK4\/6 Inhibitors at the Crossroads of Anticancer Immunity","volume":"25","author":"M Ameratunga","year":"2019","journal-title":"Clin Cancer Res"},{"issue":"9","key":"pone.0330102.ref009","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1001\/jamaoncol.2023.2000","article-title":"Cyclin-Dependent Kinase 4\/6 Inhibitors for Treatment of Hormone Receptor-Positive, ERBB2-Negative Breast Cancer: A Review","volume":"9","author":"CC O\u2019Sullivan","year":"2023","journal-title":"JAMA Oncol"},{"issue":"13","key":"pone.0330102.ref010","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1158\/1078-0432.CCR-14-0816","article-title":"Molecular Pathways: Targeting the Cyclin D-CDK4\/6 Axis for Cancer Treatment","volume":"21","author":"T VanArsdale","year":"2015","journal-title":"Clin Cancer Res"},{"issue":"47","key":"pone.0330102.ref011","doi-asserted-by":"crossref","first-page":"29227","DOI":"10.1039\/D1RA03820F","article-title":"CDK4\/6 inhibitors: a brief overview and prospective research directions","volume":"11","author":"T Adon","year":"2021","journal-title":"RSC Adv"},{"issue":"5","key":"pone.0330102.ref012","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1158\/0008-5472.CAN-20-2121","article-title":"Differential Regulation of Cancer Progression by CDK4\/6 Plays a Central Role in DNA Replication and Repair Pathways","volume":"81","author":"M Dai","year":"2021","journal-title":"Cancer Res"},{"issue":"21","key":"pone.0330102.ref013","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.1182\/blood.V118.21.3498.3498","article-title":"Targeting the Cyclin D - 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