Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Activating mutations in epidermal growth factor receptor (EGFR) are key targets in non-small-cell lung cancer (NSCLC).
• Approved EGFR tyrosine kinase inhibitors (TKIs) like osimertinib face resistance, often due to the C797S mutation.
• The C797S mutation diminishes the efficacy of covalent TKIs by disrupting the key covalent-bond-forming interaction.

Purpose of the Study:

• To optimize a reversible EGFR inhibitor with initial biochemical potency but suboptimal physicochemical properties.
• To develop a novel therapeutic agent effective against EGFR mutations, including the resistance-conferring C797S mutation.
• To identify a compound with improved cell activity, oral bioavailability, and in vivo efficacy in relevant NSCLC models.

Main Methods:

• Medicinal chemistry optimization of a lead reversible EGFR inhibitor.
• Biochemical and cellular assays to assess inhibitor potency and activity.
• Pharmacokinetic studies to evaluate oral exposure.
• In vivo efficacy studies using preclinical NSCLC xenograft models harboring specific EGFR mutations.

Main Results:

• Identification of compound 12 through systematic medicinal chemistry efforts.
• Compound 12 exhibited enhanced cell potency compared to the starting point.
• Improved oral exposure and significant in vivo anti-tumor activity were observed for compound 12.
• Efficacy was demonstrated in a challenging Exon19 deletion/T790M/C797S triple-mutant NSCLC xenograft model.

Conclusions:

• Compound 12 represents a promising, optimized reversible EGFR inhibitor.
• This compound demonstrates potential for treating NSCLC driven by complex EGFR mutations, including those conferring resistance to existing therapies.
• Further development of compound 12 may offer a new therapeutic option for patients with refractory NSCLC.