PROTACEGFRdegrader 14 is a potent and selective EGFR PROTAC degrader with a DC50 value of approximately 2.9 nM against EGFRL858R/T790M/C797S and a Dmax of 93.1%. It induces the selective degradation of EGFRC797S via a VHL and proteasome-dependent mechanism, downregulating EGFR-related transcriptomes. PROTACEGFRdegrader 14 exhibits high selectivity for EGFRWT, induces cell cycle arrest and apoptosis, and effectively inhibits tumor growth. It is applicable for research on non-small cell lung cancer (NSCLC).

PROTAC EGFR degrader 14 (Compound 9ea) effectively degrades EGFR in a concentration and dose-dependent manner in PC9 (EGFR L858R/T790M/C797S) and PC9 (EGFR Del19/T790M/C797S) cells, with DC50 values of 2.9 nM and 21.6 nM respectively, and shows no activity in EGFR wild-type cell lines (A549, DC50 = 2157 nM). When applied at 0.1-5 μM for 24-48 hours, it induces G1 phase arrest and apoptosis in the same cell lines. Additionally, at concentrations of 0.01-0.25 μM for 24 hours, PROTAC EGFR degrader 14 effectively reduces EGFR degradation in these cells through a mechanism dependent on the proteasome and VHL system.

Compound 9ea, a PROTAC EGFR degrader 14, administered intravenously at a dose of 25-50 mg/kg every other day for a total of 15 days, effectively inhibits tumor growth in a PC9 (EGFR L858R/T790M/C797S) xenograft mouse model, demonstrating significant EGFR degradation without any signs of toxicity.