HBE‐843, a Novel, Potent, and Selective EGFR Targeting PROTAC for the Treatment of Non‐Small‐Cell Lung Cancer

ABSTRACT 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 GI 50 (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 DC 50 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.