Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR L858R/T790M/C797S )

Tertiary EGFR mutation induced resistance against osimertinib ( ) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR inhibitors. A representative compound, , exhibited an IC of 27.5 nM against the EGFR mutant, while being a significantly less potent for EGFR (IC > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.