Discovery of novel potent covalent inhibitor-based EGFR degrader with excellent in vivo efficacy

[Display omitted] •A series of EGFR-PROTACs were designed, synthesized, and evaluated for their biological activities.•13 exhibited excellent anti-proliferative activities against HCC-827 cells.•13 can efficiently induce EGFR protein degradation and inhibit phosphorylation of downstream pathways in vitro and in vivo.•13 had good metabolic stability and pharmacokinetic properties.•13 is the first EGFR-PROTAC to evaluate antitumor effect in vivo, and showed excellent antitumor efficacy (TGI = 90%). Although several Epidermal growth factor receptor (EGFR) inhibitors have been approved for the treatment of non-small-cell lung cancers (NSCLC), acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology Proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Here, we reported the discovery of Dacomitinib-based EGFR degraders. Promising compound 13 can effectively induce degradation of EGFRdel19 with DC50 value of 3.57 nM in HCC-827 cells, but not to other EGFR mutant, wild-type EGFR protein and the same family receptors (HER2 and HER4). Of note, 13 is the first EGFR-PROTAC to evaluate antitumor effect in vivo, and exhibited excellent antitumor efficacy (TGI = 90%) at a dose of 30 mg/kg without causing observable toxic effects. The preliminary mechanism study demonstrated that 13 can efficiently induce EGFR protein degradation through ubiquitin proteasome pathway and inhibit phosphorylation of downstream pathways in vitro and in vivo, which indicated that 13 exerted antitumor effect by degradation of EGFR protein in tumor tissue. Overall, our study provided further evidence to validate EGFR-PROTACs as a promising strategy for lung cancer therapy.