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Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine(7)(9)(0) --> methionine(7)(9)(0) mutant

Seedson 添加于 2012-8-15 20:30 | 1712 次阅读 | 0 个评论

作者
Chang S, Zhang L, Xu S, Luo J, Lu X, Zhang Z, Xu T, Liu Y, Tu Z, Xu Y, Ren X, Geng M, Ding J, Pei D, Ding K
摘要
The EGFR(T790M) mutant contributes approximately 50% to clinically acquired resistance against gefitinib or erlotinib. However, almost all the single agent clinical trials of the second generation irreversible EGFR inhibitors appear inadequate to overcome the EGFR(T790M)-related resistance. We have designed and synthesized a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors. The most potent compounds, 2q and 2s, inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC(50) values in subnanomolar ranges, including the T790M mutants. The kinase inhibitory efficiencies of the compounds were further validated by Western blot analysis of the activation of EGFR and downstream signaling in cancer cells harboring different mutants of EGFR. The compounds also strongly inhibited the proliferation of H1975 non small cell lung cancer cells bearing EGFR(L858R/T790M), while being significantly less toxic to normal cells. Moreover, 2s displayed promising anticancer efficacy in a human NSCLC (H1975) xenograft nude mouse model.
详细资料
- 关键词: Animals; Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology; Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology; Cell Proliferation/drug effects; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms/drug therapy/metabolism/pathology; Methionine/*genetics; Mice; Mice, Nude; Mice, SCID; Molecular Conformation; Mutation; Neoplasm Transplantation; Pyrimidines/*chemical synthesis/chemistry/pharmacology; Quinazolines/pharmacology; ...
- 文献种类:期刊
- 期刊名称: Journal of Medicinal Chemistry
- 期刊缩写: J Med Chem
- 期卷页: 2012年第55卷第6期 2711-2723页
- 地址: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China
- ISBN: 0022-2623
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