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Using in silico molecular docking, Rilpivirine demonstrated a docking score of \u22127.534\u2009kcal\/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002. Molecular dynamics (MD) simulations over 200\u2009ns revealed the stability of the Rilpivirine\u2013EGFR complex, with RMSD values ranging from 2.5 to 3.5\u2009\u00c5. The in vitro antiproliferative assays showed that Rilpivirine had an IC<jats:sub>50<\/jats:sub> value of 2.3\u2009\u00b5M against H1975 cells, while WZ4002 had an IC<jats:sub>50<\/jats:sub> of 0.291\u2009\u00b5M, indicating moderate efficacy. Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC<jats:sub>50<\/jats:sub> value of 54.22\u2009nM and spared the wild\u2010type EGFR TK with an IC<jats:sub>50<\/jats:sub> of 22.52\u2009nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R\/T790M mutations<\/jats:p>","DOI":"10.1002\/jcb.30653","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T06:49:07Z","timestamp":1726814947000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Repurposing Non\u2010Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs) to Overcome EGFR T790M\u2010Mediated Acquired Resistance in Non\u2010Small Cell Lung Cancer"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7697-9572","authenticated-orcid":false,"given":"Iqrar","family":"Ahmad","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry R. C. 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