{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:22:16Z","timestamp":1770834136199,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The epidermal growth factor receptor (EGFR) is a highly attractive and promising target for novel anticancer agents, particularly for non-small-cell lung cancer (NSCLC), due to its crucial role in regulating cell survival and proliferation. Despite the development of first-generation reversible inhibitors like Gefitinib and Erlotinib, acquired resistance necessitated the discovery of highly potent irreversible inhibitors effective against drug-resistant mutants. Molecular docking calculations utilizing both EGFR conformations identified five top-ranked compounds (QN012, QN017, QN019, QN022, and QN023) proposed for synthesis and biological evaluation. These in silico studies predicted high inhibitory activity against the active and inactive state of EGFR. Herein, we report the design, synthesis and biological evaluation of novel 4-anilino quinazoline derivatives, bearing various alkynyl substituents at position 6, expected to bind to the hinge Met793 residue of EGFR. The effects of the derivatives on various cancer cell lines in terms of cytotoxic\/cytostatic activity, interference with cell cycle phase distribution, and suppression of EGFR phosphorylation set the basis for the design of more potent derivatives.<\/jats:p>","DOI":"10.3390\/ijms27041738","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T17:45:36Z","timestamp":1770831936000},"page":"1738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, Antiproliferative Potency and In Silico Studies of Novel Alkynyl Quinazolines as Potential EGFR Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Apostolia","family":"Gkoutzivelaki","sequence":"first","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sotiria-Iro","family":"Triantopoulou","sequence":"additional","affiliation":[{"name":"Institute of Nuclear & Radiological Sciences and Technology, Energy & Safety, National Centre for Scientific Research \u201cDemokritos\u201d, 15341 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7118-9942","authenticated-orcid":false,"given":"Lykourgos","family":"Chiniadis","sequence":"additional","affiliation":[{"name":"Institute of Biosciences & Applications, National Centre for Scientific Research \u201cDemokritos\u201d, 15341 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandros","family":"Komiotis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Frederick University, Nicosia 1036, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-8657","authenticated-orcid":false,"given":"Charalampos","family":"Triantis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Frederick University, Nicosia 1036, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitri","family":"Komiotis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Frederick University, Nicosia 1036, Cyprus"},{"name":"Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41335 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3931-6232","authenticated-orcid":false,"given":"Athanasios","family":"Papakyriakou","sequence":"additional","affiliation":[{"name":"Institute of Biosciences & Applications, National Centre for Scientific Research \u201cDemokritos\u201d, 15341 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7550-1975","authenticated-orcid":false,"given":"Harris","family":"Pratsinis","sequence":"additional","affiliation":[{"name":"Institute of Biosciences & Applications, National Centre for Scientific Research \u201cDemokritos\u201d, 15341 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"Manta","sequence":"additional","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/35052073","article-title":"Untangling the ErbB signalling network","volume":"2","author":"Yarden","year":"2001","journal-title":"Nat. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1600298","DOI":"10.1002\/ardp.201600298","article-title":"Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives","volume":"350","author":"Ali","year":"2017","journal-title":"Arch. Pharm. Weinh."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bioorg.2017.02.004","article-title":"Design and Synthesis of Quinazoline-3,4-(4H)-Diamine Endowed with Thiazoline Moiety as New Class for DPP-4 and DPPH Inhibitor","volume":"71","author":"Ali","year":"2017","journal-title":"Bioorg. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"a008912","DOI":"10.1101\/cshperspect.a008912","article-title":"Receptor Tyrosine Kinases: Legacy of the First Two Decades","volume":"6","author":"Schlessinger","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","article-title":"Cell Signaling by Receptor Tyrosine Kinases","volume":"141","author":"Lemmon","year":"2010","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nrc2088","article-title":"Epidermal Growth Factor Receptor Mutations in Lung Cancer","volume":"7","author":"Sharma","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1586\/14737140.4.1.5","article-title":"Gefitinib (Iressa\u00ae): A Novel Treatment for Non-Small Cell Lung Cancer","volume":"4","author":"Vansteenkiste","year":"2004","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2174\/1568011043482106","article-title":"Epidermal Growth Factor Receptor Inhibitors: A New Prospective in the Treatment of Lung Cancer","volume":"4","author":"Tiseo","year":"2004","journal-title":"Curr. Med. Chem. Anticancer Agents"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/S1470-2045(12)70087-6","article-title":"Afatinib versus Placebo for Patients with Advanced, Metastatic Non-Small-Cell Lung Cancer after Failure of Erlotinib, Gefitinib, or Both, and One or Two Lines of Chemotherapy (LUX-Lung 1): A Phase 2b\/3 Randomised Trial","volume":"13","author":"Miller","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1517\/13543784.12.8.1395","article-title":"Erlotinib: A New Therapeutic Approach for Non-Small Cell Lung Cancer","volume":"12","author":"Bonomi","year":"2003","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102932","DOI":"10.1016\/j.rechem.2025.102932","article-title":"Heterocyclic Compounds with Diverse Biological Activities: A Review of Quinazoline and Quinazolinone Derivatives","volume":"19","author":"Kalakwade","year":"2026","journal-title":"Results Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6373","DOI":"10.1016\/j.bmcl.2007.08.061","article-title":"Synthesis and Biological Evaluation of Substituted 6-Alkynyl-4-Anilinoquinazoline Derivatives as Potent EGFR Inhibitors","volume":"17","author":"Liu","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2400057","DOI":"10.1002\/ardp.202400057","article-title":"A Literature Review on Pharmacological Aspects, Docking Studies, and Synthetic Approaches of Quinazoline and Quinazolinone Derivatives","volume":"357","author":"Ghoneim","year":"2024","journal-title":"Arch. Pharm. Weinh."},{"key":"ref_14","unstructured":"Anagnostopoulos, A. (2019). Synthesis and Spectroscopic Identification of Alkynyl Substituted Quinazolines as Potential Anticancer Agents. [Bachelor\u2019s Thesis, University of Thessaly]."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8089","DOI":"10.1021\/jm1009605","article-title":"Design, Synthesis, and DNA-Binding of N-Alkyl(Anilino)Quinazoline Derivatives","volume":"53","author":"Garofalo","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1016\/j.ejmech.2009.12.078","article-title":"Synthesis, Biological Evaluation and Molecular Docking of Novel Series of Spiro [(2H,3H) Quinazoline-2,1\u2032-Cyclohexan]-4(1H)-One Derivatives as Anti-Inflammatory and Analgesic Agents","volume":"45","author":"Amin","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.1016\/j.ejmech.2010.07.067","article-title":"Synthesis, Analgesic and Anti-Inflammatory Evaluation of Some Novel Quinazoline Derivatives","volume":"45","author":"Alafeefy","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s00044-020-02656-8","article-title":"Pyrimidine and Fused Pyrimidine Derivatives as Promising Protein Kinase Inhibitors for Cancer Treatment","volume":"30","author":"Abdellatif","year":"2021","journal-title":"Med. Chem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.bioorg.2016.03.011","article-title":"Design, Synthesis and Antitumor Activity of Novel Pyrazolo[3,4-d]Pyrimidine Derivatives as EGFR-TK Inhibitors","volume":"66","author":"Abdelgawad","year":"2016","journal-title":"Bioorg. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1016\/j.ejmech.2011.03.015","article-title":"Synthesis and in Vitro Antitumor Activity of Substituted Quinazoline and Quinoxaline Derivatives: Search for Anticancer Agent","volume":"46","author":"Noolvi","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"733","DOI":"10.3109\/14756366.2013.845820","article-title":"Synthesis and Characterization of Quinazoline Derivatives: Search for Hybrid Molecule as Diuretic and Antihypertensive Agents","volume":"29","author":"Rahman","year":"2014","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.bbamem.2011.11.026","article-title":"Effects of an Antimalarial Quinazoline Derivative on Human Erythrocytes and on Cell Membrane Molecular Models","volume":"1818","author":"Sotomayor","year":"2012","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1248\/cpb.55.1615","article-title":"Synthesis and Antimicrobial Activities of Some Novel Substituted 2-Imidazolyl-N-(4-Oxo-Quinazolin-3(4H)-Yl)-Acetamides","volume":"55","author":"Raghavendra","year":"2007","journal-title":"Chem. Pharm. Bull."},{"key":"ref_24","first-page":"136","article-title":"Quinazolines: An Illustrated Review","volume":"3","author":"Pati","year":"2013","journal-title":"J. Adv. Pharm. Edu. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.3390\/molecules13102557","article-title":"Synthesis and Anticonvulsant Activity of Some Quinazolin-4-(3H)-One Derivatives","volume":"13","author":"Georgey","year":"2008","journal-title":"Molecules"},{"key":"ref_26","first-page":"267","article-title":"Synthesis And Microbial Studies Of (4-Oxo-Thiazolidinyl) Sulfonamides Bearing Quinazolin-4(3H)Ones","volume":"67","author":"Patel","year":"2010","journal-title":"Acta Pol. Pharm. \u00f1 Drug Res."},{"key":"ref_27","first-page":"1035","article-title":"Synthesis, In Silico Pharmacokinetic Profile and Anti-Cholinesterase Activity of Quinazolin-4(3H)-One Derivatives","volume":"63","author":"Sarfraz","year":"2018","journal-title":"Rev. Roum. Chim."},{"key":"ref_28","first-page":"62","article-title":"Synthesis and Evaluation of Antioxidant Activities of Novel Quinazolinone Derivatives","volume":"6","author":"Saravanan","year":"2010","journal-title":"Int. J. Res. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.ejmech.2016.12.005","article-title":"2,4-Disubstituted Quinazolines as Amyloid-\u03b2 Aggregation Inhibitors with Dual Cholinesterase Inhibition and Antioxidant Properties: Development and Structure-Activity Relationship (SAR) Studies","volume":"126","author":"Mohamed","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1200\/JCO.2012.45.0981","article-title":"LUX-Lung 4: A Phase Ii Trial of Afatinib in Patients with Advanced Non-Small-Cell Lung Cancer Who Progressed during Prior Treatment with Erlotinib, Gefitinib, or Both","volume":"31","author":"Katakami","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8249","DOI":"10.1021\/jm500973a","article-title":"Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor","volume":"57","author":"Finlay","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"46265","DOI":"10.1074\/jbc.M207135200","article-title":"Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor","volume":"277","author":"Stamos","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"18756","DOI":"10.1074\/jbc.M110.206193","article-title":"Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein","volume":"286","author":"Aertgeerts","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1021\/acsmedchemlett.8b00314","article-title":"C797S Resistance: The Undruggable EGFR Mutation in Non-Small Cell Lung Cancer?","volume":"9","author":"Grabe","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34979","DOI":"10.1074\/jbc.M112.374504","article-title":"The Methionine-Aromatic Motif Plays a Unique Role in Stabilizing Protein Structure","volume":"287","author":"Valley","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6818","DOI":"10.1073\/pnas.1814279116","article-title":"Defining a New Nomenclature for the Structures of Active and Inactive Kinases","volume":"116","author":"Modi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","first-page":"564","article-title":"Synthesen von Chinazolinverbindungen","volume":"51","year":"1894","journal-title":"J. F\u00fcr Prakt. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/S0022-328X(02)01158-0","article-title":"Mini Account Development of Pd-Cu Catalyzed Cross-Coupling of Terminal Acetylenes with Sp 2-Carbon Halides","volume":"653","author":"Sonogashira","year":"2002","journal-title":"J. Organomet. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1126\/science.6200934","article-title":"Amplification and Enhanced Expression of the Epidermal Growth Factor Receptor Gene in A431 Human Carcinoma Cells","volume":"224","author":"Merlino","year":"1984","journal-title":"Science"},{"key":"ref_40","first-page":"5201","article-title":"Epidermal Growth Factor Receptor Expression Affects Proliferation and Apoptosis in Non-Small Cell Lung Cancer Cells via the Extracellular Signal-Regulated Kinase\/MicroRNA 200a Signaling Pathway","volume":"15","author":"Zhou","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7201","DOI":"10.1038\/s41598-017-07489-x","article-title":"Chemotherapy Treatment Induces an Increase of Autophagy in the Luminal Breast Cancer Cell MCF7, but Not in the Triple-Negative MDA-MB231","volume":"7","author":"Garbar","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/bjc.1998.142","article-title":"Epidermal Growth Factor Receptor Activation in Androgen-Independent but Not Androgen-Stimulated Growth of Human Prostatic Carcinoma Cells","volume":"77","author":"Sherwood","year":"1998","journal-title":"Br. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.3892\/ijmm.2015.2088","article-title":"Epidermal Growth Factor Improves the Migration and Contractility of Aged Fibroblasts Cultured on 3D Collagen Matrices","volume":"35","author":"Kim","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1097\/JTO.0b013e3180f60bb3","article-title":"Schedule-Dependent Interaction between the Proteosome Inhibitor Bortezomib and the EGFR-TK Inhibitor Erlotinib in Human Non-Small Cell Lung Cancer Cell Lines","volume":"2","author":"Piperdi","year":"2007","journal-title":"J. Thorac. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1016\/j.bcp.2005.09.007","article-title":"EGFR Blockade by Cetuximab Alone or as Combination Therapy for Growth Control of Hepatocellular Cancer","volume":"70","author":"Huether","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1021\/ja01847a024","article-title":"Nuclear Iodination of Aromatic Amines Matic Amines and Iodine Have Been Carried out By","volume":"63","author":"Militzer","year":"1941","journal-title":"J. Am. Chem. Soc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7964","DOI":"10.1039\/D4RA00502C","article-title":"Anticancer Evaluations of Iodoquinazoline Substituted with Allyl and\/or Benzyl as Dual Inhibitors of EGFRWT and EGFRT790M: Design, Synthesis, ADMET and Molecular Docking","volume":"14","author":"Aljohani","year":"2024","journal-title":"RSC Adv."},{"key":"ref_48","first-page":"457","article-title":"Synthesis, Analgesic and Anti-Inflammatory Activities of Some New Fenamate Analogues","volume":"58","author":"Alafeefy","year":"2008","journal-title":"Arzneimittelforschung"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1021\/jm400349k","article-title":"Kinase Scaffold Repurposing for Neglected Disease Drug Discovery: Discovery of an Efficacious, Lapatanib-Derived Lead Compound for Trypanosomiasis","volume":"56","author":"Patel","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5531","DOI":"10.1016\/j.bmcl.2009.08.064","article-title":"Discovery and Structure-Activity Relationships of a Novel Class of Quinazoline Glucokinase Activators","volume":"19","author":"Iino","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e14422","DOI":"10.1111\/acel.14422","article-title":"A Subset of Human Dermal Fibroblasts Overexpressing Cockayne Syndrome Group B Protein Resist UVB Radiation-Mediated Premature Senescence","volume":"24","author":"Fotopoulou","year":"2025","journal-title":"Aging Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.ejmech.2006.10.008","article-title":"Pyrimido[4,5-c]Quinolin-1(2H)-Ones as a Novel Class of Antimitotic Agents: Synthesis and in Vitro Cytotoxic Activity","volume":"42","author":"Metwally","year":"2007","journal-title":"Eur. J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Software News and Updates AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/ci100031x","article-title":"Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database","volume":"50","author":"Hawkins","year":"2010","journal-title":"J. Chem. Inf. Model."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1738\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T17:46:31Z","timestamp":1770831991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041738"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041738","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]}}}