Background: In non-small cell lung cancer, T790M mutation is the leading cause
of acquired resistance to the first generation EGFR inhibitors including gefitinib, erlotinib and
Methods: Herein, we describe a novel series of oxopyrido[2,3?d]pyrimidine-7-ones derivatives
as T790M-mutant EGFR selective inhibitors. Twenty-one new compounds were designed and synthesized.
Results: Compound 9a demonstrated potent inhibition of EGFRL858R/T790M (IC50 = 124.9 nM)
with no inhibitory activity against EGFRWT (IC50 > 10000 nM). Compound 9a showed moderate
proliferative inhibition to NCI-H1975 adenocarcinoma cell line and improved pharmacokinetic
properties compared to the lead compound 6. In an NCI-H1975 murine xenograft model, 9a
exhibited >50% tumor inhibition at 30 mg/kg.
Conclusion: Compound 9a may serve as a promising lead compound for further drug discovery.
Keywords: NSCLC, Irreversible inhibitors, EGFRT790M mutant, Anti-tumor
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