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

Abstract

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 IC₅₀ of 27.5 nM against the EGFR^{L858R/T790M/C797S} mutant, while being a significantly less potent for EGFR^WT (IC₅₀ > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.