Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine790 鈫?Methionine790 Mutant

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• 作者：Shaohua Chang ; Lianwen Zhang ; Shilin Xu ; Jinfeng Luo ; Xiaoyun Lu ; Zhang Zhang ; Tianfeng Xu ; Yingxue Liu ; Zhengchao Tu ; Yong Xu ; Xiaomei Ren ; Meiyu Geng ; Jian Ding ; Duanqing Pei ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2711-2723
• 全文大小：465K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

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 IC₅₀ 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.