Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Drug resistance mutations, particularly C797S, pose a significant challenge for non-small cell lung cancer (NSCLC) treatment with epidermal growth factor receptor (EGFR) inhibitors like osimertinib.
• The C797S mutation in EGFR disrupts the binding of covalent inhibitors, leading to reduced drug efficacy and treatment failure.

Purpose of the Study:

• To develop novel, reversible EGFR inhibitors capable of overcoming the C797S resistance mutation.
• To design next-generation inhibitors that maintain high potency against EGFR mutations associated with osimertinib resistance.

Main Methods:

• Combining the methylindole-aminopyrimidine scaffold of osimertinib with the isopropyl ester moiety of mobocertinib to create novel reversible inhibitors.
• Evaluating the inhibitory activity of the newly designed compounds against EGFR variants, including EGFR-L858R/C797S and EGFR-L858R/T790M/C797S.
• Determining the cellular activity of inhibitors using Ba/F3 cells dependent on EGFR-L858R/C797S.
• Resolving cocrystal structures of the reversible aminopyrimidine inhibitors bound to EGFR.

Main Results:

• The novel reversible inhibitors demonstrated subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S mutations.
• Cellular assays confirmed the efficacy of these inhibitors against EGFR-L858R/C797S-driven Ba/F3 cells.
• Cocrystal structures revealed the binding mode of these inhibitors, highlighting their interaction with the hydrophobic back pocket of EGFR.

Conclusions:

• The developed reversible EGFR inhibitors effectively overcome the C797S resistance mutation, a key mechanism limiting osimertinib efficacy in NSCLC.
• These findings provide a foundation for designing advanced EGFR inhibitors tailored to combat resistance mutations in personalized cancer therapy.
• Structural insights from cocrystal analysis will guide the optimization of future inhibitors targeting C797S-mutated EGFR.