School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China; Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Guangzhou 510000, PR China.
Eur J Med Chem. 2021 Feb 15;212:113019. doi: 10.1016/j.ejmech.2020.113019. Epub 2020 Nov 13.
Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
肺癌是癌症死亡的主要原因。已经证明，表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）对 EGFR 突变阳性非小细胞肺癌（NSCLC）患者有效。在这项工作中，设计、合成并评价了一系列新型含环丙基部分的 2,4-二芳基嘧啶衍生物作为新型选择性 EGFR 抑制剂。最有前途的化合物 8l 对 EGFR 双突变显示出优异的激酶抑制活性，IC 值为 0.26 nM。此外，8l 对 H1975 细胞具有强活性，IC 值为 0.008 μM，对四种非肿瘤细胞系的毒性很小。此外，8l 在 EGFR 驱动的 H1975 异种移植模型中表现出很强的抗肿瘤疗效。这些结果表明，8l 可能是进一步研究的有前途的候选药物。
