Design, synthesis, and evaluation of dual EGFR/AURKB inhibitors as anticancer agents for non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard treatment for mutant EGFR-positive (mEGFR+) non-small cell lung cancer (NSCLC).
• Acquired resistance mutations in EGFR (rmEGFR+) and co-occurring Kirsten rat sarcoma virus protein mutations (mKRAS+) render EGFR-TKIs ineffective.
• Aurora kinase B (AURKB) is implicated in NSCLC proliferation and survival, presenting a potential therapeutic target.

Purpose of the Study:

• To develop novel dual inhibitors targeting both EGFR and AURKB to overcome resistance mechanisms in NSCLC.
• To identify compounds effective against rmEGFR+ and mKRAS+ NSCLC.
• To evaluate the potential of combined EGFR and AURKB inhibition for improved anticancer effects.

Main Methods:

• Utilized molecular modeling to identify structural similarities between EGFR and AURKB kinase pockets.
• Synthesized a series of compounds (3-7) designed as dual EGFR/AURKB inhibitors.
• Assessed the inhibitory activity of synthesized compounds against rmEGFR+ and mKRAS+ NSCLC cells.

Main Results:

• Compounds 5, 6, and 7 were identified as dual EGFR/AURKB inhibitors.
• Compound 5 showed modest micromolar inhibition against rmEGFR+ NSCLC.
• Compound 7 exhibited single-digit micromolar inhibition against mKRAS+ NSCLC cells, with all compounds demonstrating moderate inhibition of mKRAS+ NSCLC cells.

Conclusions:

• Dual EGFR/AURKB inhibitors represent a promising therapeutic strategy for NSCLC with EGFR resistance mutations or KRAS mutations.
• The synthesized compounds demonstrate potential for overcoming acquired resistance to EGFR-TKIs.
• Further development of these dual inhibitors could lead to more effective treatments for refractory NSCLC.