{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:53:47Z","timestamp":1791356027177,"version":"4.3.1"},"reference-count":58,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A unique series of 1,2,4\u2010triazolo[1,5\u2010\n                    <jats:italic>a<\/jats:italic>\n                    ]pyrimidine derivatives was designed and synthesized as potential dual inhibitors of EGFR and CDK\u20102 to circumvent drug resistance in colorectal cancer patients through multi\u2010targeted therapy. When tested against HCT\u2010116 colorectal carcinoma cells, these compounds showed anticancer activity with lower toxicity against normal cells, thus providing a high selectivity index (&gt;\u20092). Leads\n                    <jats:bold>12c<\/jats:bold>\n                    ,\n                    <jats:bold>12i<\/jats:bold>\n                    , and\n                    <jats:bold>22<\/jats:bold>\n                    demonstrated potent kinase inhibition, with\n                    <jats:bold>22<\/jats:bold>\n                    yielding a CDK\u20102 IC\u2085\u2080 of 0.03\u2009\u00b5M (seliciclib: 0.02\u2009\u00b5M), and\n                    <jats:bold>12c<\/jats:bold>\n                    delivering an EGFR IC\u2085\u2080 of 0.12\u2009\u00b5M (erlotinib: 0.01\u2009\u00b5M). These leads induced G\n                    <jats:sub>2<\/jats:sub>\n                    \/M cell cycle arrest and apoptosis in HCT\u2010116 cells via upregulation of Bax, cytochrome c, and caspase\u20103, and downregulation of VEGF, AKT\u20101, and Bcl\u20102. Network pharmacology suggested EGFR and CDK\u20102 as key targets. Redocking reference ligands erlotinib (EGFR, PDB: 1M17) and seliciclib (CDK\u20102, PDB: 2A4L) confirmed docking poses, and binding interactions of\n                    <jats:bold>12c<\/jats:bold>\n                    and\n                    <jats:bold>22<\/jats:bold>\n                    matched those of references. Using 100\u2010ns molecular dynamics simulations proved the stability of ligand\u2010protein complexes and further supported the reliability of predicted binding modes. Promising ADMET profiles and good drug likeness are evident in these leads. These data underscore the great potential of this scaffold for developing dual EGF\/CDK\u20102 inhibitors aimed at resistance mechanisms in more aggressive cancers and can thus be pursued further in preclinical optimization.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70323","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:27:42Z","timestamp":1779881262000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lead Discovery\n                    <i>via<\/i>\n                    Scaffold Refinement: Structure\u2010Guided Optimization of 1,2,4\u2010Triazolo[1,5\u2010\n                    <i>a<\/i>\n                    ]Pyrimidines as Potent Dual EGFR\/CDK\u20102 Inhibitors Targeting Colorectal Carcinoma"],"prefix":"10.1002","volume":"87","author":[{"given":"Rowida","family":"Nasr","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9924-2063","authenticated-orcid":false,"given":"Hesham","family":"Haffez","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Faculty of Pharmacy Capital University (formerly Helwan University) Cairo Egypt"},{"name":"Helwan Structural Biology Center for Excellence Capital University (formerly Helwan University) Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4454-6390","authenticated-orcid":false,"given":"Mohamed S.","family":"Nafie","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Sciences University of Sharjah Sharjah United Arab Emirates"},{"name":"Chemistry Department, Faculty of Science Suez Canal University Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Ahmed A.","family":"Moustafa","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M.","family":"El\u2010kerdawy","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1719-6199","authenticated-orcid":false,"given":"Ahmed R.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169442"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26020506"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4RA06704E"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.30344"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232416091"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2006.10.004"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112640"},{"key":"e_1_2_13_9_1","article-title":"Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters","author":"Bowers K. 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