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

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Drug resistance to EGFR-TKIs is a major challenge in non-small-cell lung cancer (NSCLC) treatment.
• EGFR mutations, such as L858R/T790M and del19, drive tumor growth and confer resistance.
• Novel therapeutic strategies are needed to overcome EGFR-TKI resistance in NSCLC.

Purpose of the Study:

• To develop novel proteolysis targeting chimeras (PROTACs) to degrade drug-resistant EGFR mutants.
• To optimize covalent EGFR ligands for enhanced PROTAC efficacy.
• To investigate the potential of covalent PROTACs in overcoming EGFR-TKI resistance in NSCLC.

Main Methods:

• Design and synthesis of covalent and reversible covalent pyrimidine- or purine-containing PROTACs targeting EGFR mutants.
• Evaluation of PROTACs' degradation potency (DC50) against EGFR mutants.
• Assessment of cellular activity and selectivity in NSCLC cell lines (H1975, HCC827).
• Investigation of the cellular degradation mechanism, including lysosomal involvement.

Main Results:

• Discovery of covalent PROTAC CP17 with a novel purine-containing EGFR ligand.
• CP17 demonstrated potent degradation of EGFR^L858R/T790M and EGFR^del19 with the lowest DC50 values reported for EGFR-targeting PROTACs.
• CP17 exhibited excellent cellular activity and high selectivity against H1975 and HCC827 cell lines.
• Lysosomal pathways were implicated in the PROTAC-mediated degradation process.

Conclusions:

• Covalent PROTACs, exemplified by CP17, are effective in degrading drug-resistant EGFR mutants.
• The covalent binding strategy is a viable approach for designing potent EGFR-targeting PROTACs.
• This study provides a foundation for developing advanced PROTAC-based therapies for EGFR-mutated NSCLC.