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The emergence of the EGFR C797S mutation poses a significant challenge in the treatment of non-small cell lung cancer due to resistance to third-generation EGFR-tyrosine kinase inhibitors. This study introduces a novel and highly selective EGFR PROTAC, HBE-843, designed to degrade mutant EGFR while sparing wild-type 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 GI₅₀ (26-103 nM) across all these EGFR mutant-harboring cell lines while sparing the wild-type. HBE-843 effectively reduced EGFR protein levels in mutant cells in a dose-dependent manner, with a DC₅₀ in the low nanomolar range (1.9-18 nM) and a D_max above 90%. Mechanistic studies showed that HBE-843 mediates EGFR degradation through the CRBN-associated 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-induced cancers. These findings suggest that HBE-843 holds promise as a lead compound for developing new drugs to overcome C797S mutant-mediated resistance in clinical settings.