基于结构的 C4-烷基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]恶嗪-2-酮类作为有效且突变选择性的表皮生长因子受体（EGFR）L858R/T790M 抑制剂的设计。

Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors.

机构信息

State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai, 200237, China.

Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

出版信息

Sci Rep. 2017 Jun 19;7(1):3830. doi: 10.1038/s41598-017-04184-9.

Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR (H1975 cell lines) over EGFR (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR. These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.

表皮生长因子受体（EGFR）T790M 获得性耐药突变已成为非小细胞肺癌治疗的主要临床挑战。在这里，我们在前一份报告的 EGFR 抑制剂（化合物 9）的基础上应用了一种基于结构的方法，并设计了一系列 C4-烷基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]恶嗪-2-酮衍生物作为新型的突变选择性 EGFR 抑制剂。最后，确定了最具代表性的化合物 20a，它在酶水平和细胞水平上对 EGFR（H1975 细胞系）均表现出高选择性，而对 EGFR（A431 细胞系）则没有选择性。代表性化合物 20a 在 EGFR 驱动的 H1975 异种移植小鼠模型的体内抗肿瘤疗效研究中也显示出有希望的抗肿瘤效率。这些结果为治疗双突变驱动的非小细胞肺癌提供了新的结构骨架。