Discovery of 2,4,6-trisubstitued pyrido[3,4-d]pyrimidine derivatives as new EGFR-TKIs

Targeting acquired drug resistance is the major challenge in the treatment of EGFR-driven non-small cell lung cancer (NSCLC). In this study, a novel class of compounds containing pyrido[3,4-d]pyrimidine scaffold was designed as new generation EGFR-TKIs to overcome this challenge. The most promising compound B30 inhibited HCC827 and H1975 cells growth with the IC₅₀ values of 0.044 μM and 0.40 μM, respectively. Meanwhile, B30 displayed potent inhibitory activity against the EGFR^L858R (IC₅₀ = 1.1 nM) and EGFR^{L858R/T790M/C797S} (IC₅₀ = 7.2 nM). B30 could suppress EGFR phosphorylation in a dose-dependent manner in HCC827 cell line and significantly induce the apoptosis of HCC827 cells. Molecular docking indicated that the hydroxyl in B30 could form additional hydrogen bond with mutant Ser797. These findings strongly support our assumption that 2,4,6-trisubstitued pyrido[3,4-d] pyrimidine derivatives can serve as EGFR-TKIs. The predicted hydrogen bond interaction formed by a small molecule inhibitor with mutant Ser797 is available to design the fourth-generation EGFR-TKIs.