Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands

Drug resistance caused by epidermal
growth factor receptor (EGFR)
mutation has largely limited the clinical use of EGFR tyrosine kinase
inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer
(NSCLC). Herein, to overcome the intractable problem of drug resistance,
proteolysis targeting chimeras (PROTACs) targeting EGFR mutants were
developed by optimizing covalent EGFR ligands. Covalent or reversible
covalent pyrimidine- or purine-containing PROTACs were designed, synthesized,
and evaluated. As a consequence, covalent PROTAC CP17, with a novel purine-containing EGFR ligand, was discovered as a
highly potent degrader against EGFRL858R/T790M and EGFRdel19, reaching the lowest DC50 values among all
reported EGFR-targeting PROTACs. Furthermore, CP17 exhibited
excellent cellular activity against the H1975 and HCC827 cell lines
with high selectivity. Mechanism investigation indicated that the
lysosome was involved in the degradation process. Importantly, the
covalent binding strategy was proven to be an effective approach for
the design of PROTACs targeting EGFRL858R/T790M, which
laid the practical foundation for further development of potent EGFR-targeting
PROTACs.