Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7- ones Derivatives as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

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Author(s): Ao Niu, Yang Wang, Yushe Yang*, Jianhai Wei, Jian Ding, Yi Chen, Linjiang Tong, Hua Xie.

Journal Name: Letters in Drug Design & Discovery

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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 icotinib. 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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(E-pub Ahead of Print)
DOI: 10.2174/1570180815666180523090558
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