Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

Tertiary EGFR C797S mutation induced resistance against osimertinib ( 1 ) 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 L858R/T790M/C797S inhibitors. A representative compound, 8r-B, exhibited an IC 50 of 27.5 nM against the EGFR L858R/T790M/C797S mutant, while being a significantly less potent for EGFR WT (IC 50 > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.