Direct Ser797 Interacted Pteridine-7(8)-one Derivatives as Highly Selective and Orally Available EGFR Inhibitors.

The EGFR mutation is the main mechanism of acquired resistance to Osimertinib in NSCLC. There is an urgent need for small-molecule inhibitors to overcome Osimertinib-resistance. In this article, we developed a series of pteridin-7(8)-one-derived inhibitors of EGFR (EGFR) integrating direct interactions with the mutated Ser797 residue and the hydrophobic pocket encircled by the gatekeeper Met790 residue. Among them, exhibited potent inhibitory activity against EGFR (IC = 18.94 nM) and showed great kinase selectivity (S(35) = 0.005). Pharmacokinetic studies revealed that orally dosed at 10 mg/kg resulted in a Cmax of 230.07 ng/mL and oral bioavailability of 12.14%. Moreover, demonstrated effective antitumor efficacy in BaF3-EGFR xenograft model in comparison with Brigatinib (TGI = 73.53% vs 56.05%). In all, this study provided a novel EGFR inhibitor discovery strategy and a pteridin-7(8)-one-based EGFR inhibitor which exhibited great potency and selectivity both and .