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This study reports the design, synthesis, and biological evaluation of triazole\u2010clubbed pyrimidine derivatives (<jats:bold>RDa<\/jats:bold>\u2013<jats:bold>RDm<\/jats:bold>) as potential anticancer agents. Thirteen compounds were synthesized and screened against the A549 lung cancer cell line. <jats:bold>RDg<\/jats:bold> emerged as the most potent derivative, exhibiting an IC<jats:sub>50<\/jats:sub> of 15.70\u2009\u00b5M, compared with the standard drug erlotinib (IC<jats:sub>50<\/jats:sub>\u2009=\u200910.10\u2009\u00b5M). Notably, all derivatives displayed moderate to excellent anticancer activity at 100\u2009\u00b5M, with IC<jats:sub>50<\/jats:sub> values ranging from 15.70 to 88.27\u2009\u00b5M. <jats:bold>RDg<\/jats:bold>, characterised by a 4\u2010chlorophenyl group, demonstrated strong in vitro activity and induced cell\u2010cycle arrest at the sub\u2010G0 phase. In vivo study using the Ehrlich ascites carcinoma (EAC) mouse model confirmed the superior anticancer efficacy of <jats:bold>RDg<\/jats:bold>. At a 5\u2009mg\/kg dose, <jats:bold>RDg<\/jats:bold> achieved a 52% reduction in tumour volume and 54% reduction in tumour weight compared with erlotinib 26% tumour volume reduction. Furthermore, <jats:bold>RDg<\/jats:bold> demonstrated a 90% tumour inhibition rate compared with erlotinib 75%, attributed to its enhanced cellular uptake and sustained release properties. In silico analyses provided insights into <jats:bold>RDg<\/jats:bold> mechanism of action, revealing strong interactions with EGFR binding sites, including hydrogen bonding with Met\u2010793 and \u03c0\u2010sulphur interaction with Met\u2010790. Molecular dynamics simulations demonstrated <jats:bold>RDg<\/jats:bold> stabilising effect on EGFR, as evidenced by reduced protein flexibility and compact conformational space. The combination of promising in vitro, in vivo and in silico results showed <jats:bold>RDg<\/jats:bold> may be used as a lead compound for further development of novel compounds as EGFR inhibitors.<\/jats:p>","DOI":"10.1002\/ddr.70154","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T10:52:57Z","timestamp":1757328777000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Triazole\u2010Pyrimidine Hybrids as EGFR Inhibitors via Synthesis, In Silico, In Vitro, and In Vivo Evaluation as Anticancer Agents"],"prefix":"10.1002","volume":"86","author":[{"given":"Rahul","family":"Dubey","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry ISF College of Pharmacy Moga Punjab 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