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This study introduces a novel and highly selective EGFR PROTAC, HBE\u2010843, designed to degrade mutant EGFR while sparing wild\u2010type EGFR. Our degrader not only effectively degrades the L858R but also shows promising activity against exon 19 deletion, T790M, and C797S, where it demonstrated low nanomolar GI\n                    <jats:sub>50<\/jats:sub>\n                    (26\u2013103\u2009nM) across all these EGFR mutant\u2010harboring cell lines while sparing the wild\u2010type. HBE\u2010843 effectively reduced EGFR protein levels in mutant cells in a dose\u2010dependent manner, with a DC\n                    <jats:sub>50<\/jats:sub>\n                    in the low nanomolar range (1.9\u201318\u2009nM) and a\n                    <jats:italic>D<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    above 90%. Mechanistic studies showed that HBE\u2010843 mediates EGFR degradation through the CRBN\u2010associated proteasome pathway, preventing the activation of the ERK downstream signal and hindering cell growth. In vivo studies demonstrated a 112% tumor growth inhibition in L858R\u2010induced cancers. These findings suggest that HBE\u2010843 holds promise as a lead compound for developing new drugs to overcome C797S mutant\u2010mediated resistance in clinical settings.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70193","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T06:47:51Z","timestamp":1770187671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["HBE\u2010843, a Novel, Potent, and Selective EGFR Targeting PROTAC for the Treatment of Non\u2010Small\u2010Cell Lung Cancer"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8227-4838","authenticated-orcid":false,"given":"Mohammad Hassan","family":"Baig","sequence":"first","affiliation":[{"name":"BNJ Biopharma Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9216-6966","authenticated-orcid":false,"given":"Chang Joong","family":"Kim","sequence":"additional","affiliation":[{"name":"BNJ Biopharma Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nale Sagar","family":"Dattatraya","sequence":"additional","affiliation":[{"name":"BNJ Biopharma Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo Yun","family":"Seong","sequence":"additional","affiliation":[{"name":"BNJ Biopharma Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhan","family":"Bok","sequence":"additional","affiliation":[{"name":"Handok Inc. 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