PROTACEGFRdegrader 9 (Compound C6) is an orally active, CRBN-based PROTAC EGFR degrader. It has a DC50 of 10.2 nM and a Kd of 240.2 nM against EGFRL858R/T790M/C797S. PROTACEGFRdegrader 9 demonstrates effective degradation activity against various EGFR mutants while not affecting EGFRWT.

PROTAC EGFR degrader 9 (Compound C6) exhibits DC50 values of 36.5, 88.5, 75.4, and >300 nM against EGFR Del19/T790M/C797S, EGFR L858R/T790M, EGFR Del19, and EGFR WT, respectively. This compound, within the concentration range of 1.2-300 nM over 24 hours, degrades the EGFR L858R/T790M/C797S protein in H1975-TM cells in a dose-dependent manner. It significantly inhibits growth in PC-9-TMb cells (containing EGFR Del19/T790M/C797S), H1975, PC-9, and A549 cells, with IC50 values of 43.5 nM, 46.2 nM, 17.5 nM, and 97.5 nM, respectively. Additionally, PROTAC EGFR degrader 9 (at 5-20 nM over 24 hours) induces cell cycle arrest in the G0/G1 phase in H1975-TM cells and promotes apoptosis in a concentration-dependent manner.

PROTAC EGFR degrader 9 (Compound C6; 25-100 mg/kg; oral administration; once daily; for 31 days) significantly reduces EGFR protein levels in tumor tissue, inhibits EGFR phosphorylation, and blocks the activation of downstream signaling pathways.