Design, synthesis and evaluation of new pyrimidine derivatives as EGFR^C797S tyrosine kinase inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• EGFR-TKIs are crucial for non-small cell lung cancer (NSCLC) treatment.
• Acquired resistance to EGFR-TKIs, particularly the EGFR^C797S mutation, limits clinical efficacy.
• Novel therapeutic strategies are needed to overcome EGFR^C797S-mediated resistance.

Purpose of the Study:

• To design and synthesize novel 2-aminopyrimidine derivatives as potent EGFR^C797S-TKIs.
• To evaluate the anti-proliferative activity and selectivity of synthesized compounds against NSCLC cells harboring EGFR^C797S mutation.
• To elucidate the molecular mechanism of action for promising drug candidates.

Main Methods:

• Chemical synthesis of 2-aminopyrimidine derivatives.
• In vitro anti-proliferative assays against NSCLC cell lines (KC-0116).
• Western blotting to assess EGFR phosphorylation inhibition.
• Cell cycle analysis to determine cell cycle arrest.
• Molecular docking simulations to predict binding interactions with EGFR.

Main Results:

• Compounds A5 and A13 exhibited significant anti-proliferative activity and high selectivity against the KC-0116 (EGFR^{del19/T790M/C797S}) cell line.
• Compound A5 effectively inhibited EGFR phosphorylation and induced apoptosis in KC-0116 cells.
• A5 treatment resulted in G2/M phase cell cycle arrest.
• Molecular docking revealed that A5 binds to EGFR similarly to brigatinib, forming key hydrogen bonds with Met793 and Lys745 residues.

Conclusions:

• Compound A5 is a potent and selective reversible EGFR^C797S-TKI.
• A5 demonstrates promising therapeutic potential for NSCLC patients with EGFR^C797S mutations.
• Further preclinical development of A5 is warranted.