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

The EGFR^C797S 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(8H)-one-derived inhibitors of EGFR^{L858R/T790M/C797S} (EGFR^LR/TM/CS) integrating direct interactions with the mutated Ser797 residue and the hydrophobic pocket encircled by the gatekeeper Met790 residue. Among them, M49 exhibited potent inhibitory activity against EGFR^LR/TM/CS (IC₅₀ = 18.94 nM) and showed great kinase selectivity (S(35) = 0.005). Pharmacokinetic studies revealed that orally dosed M49 at 10 mg/kg resulted in a Cmax of 230.07 ng/mL and oral bioavailability of 12.14%. Moreover, M49 demonstrated effective antitumor efficacy in BaF3-EGFR^{L858R/T790M/C797S} xenograft model in comparison with Brigatinib (TGI = 73.53% vs 56.05%). In all, this study provided a novel EGFR^LR/TM/CS inhibitor discovery strategy and a pteridin-7(8H)-one-based EGFR^LR/TM/CS inhibitor which exhibited great potency and selectivity both in vitro and in vivo.