Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR<sup>L858R/T790M/C797S</sup>).
Shen J, Zhang T, Zhu SJ, Sun M, Tong L, Lai M, Zhang R, Xu W, Wu R, Ding J, Yun CH, Xie H, Lu X, Ding K.
Tertiary EGFR<sup>C797S</sup> mutation induced resistance against osimertinib (<b>1</b>) 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<sup>L858R/T790M/C797S</sup> inhibitors. A representative compound, <b>8r-B</b>, exhibited an IC<sub>50</sub> of 27.5 nM against the EGFR<sup>L858R/T790M/C797S</sup> mutant, while being a significantly less potent for EGFR<sup>WT</sup> (IC<sub>50</sub> > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.