Discovery and optimization of covalent EGFR T790M/L858R mutant inhibitors

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) inhibitors are vital for treating non-small cell lung cancer (NSCLC).
• Acquired resistance, often via T790M or L858R mutations, limits the long-term efficacy of EGFR inhibitors in NSCLC patients.
• Wild-type EGFR inhibition can cause dose-limiting toxicities like rash and diarrhea.

Purpose of the Study:

• To identify and characterize a novel mutant-selective EGFR inhibitor.
• To develop a compound that targets specific resistance mutations (T790M/L858R) while sparing wild-type EGFR.

Main Methods:

• Identification of a lead compound (compound 12) through drug discovery screening.
• Characterization of compound 12 as an irreversible covalent inhibitor.
• Evaluation of selectivity for mutant EGFR (T790M/L858R) over wild-type EGFR.
• Assessment of anti-tumor activity in preclinical NSCLC models.

Main Results:

• Compound 12 was identified as a potent, irreversible covalent inhibitor of EGFR.
• The compound demonstrated significant selectivity for EGFR harboring T790M and/or L858R mutations compared to wild-type EGFR.
• Compound 12 exhibited substantial tumor growth inhibition in preclinical models of NSCLC.

Conclusions:

• Compound 12 represents a promising therapeutic candidate for NSCLC patients with acquired resistance mutations.
• The mutant-selective inhibition profile of compound 12 may overcome resistance mechanisms and reduce wild-type related toxicities.