First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFR^L858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that 20g might be used as a promising lead compound for further structural optimization as potent and selective EGFR^L858R/T790M inhibitors.

中文翻译：

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嘧啶并[4,5 - d ]嘧啶-2,4（1 H，3 H）-二酮类化合物作为针对L858R / T790M耐药突变的有效和选择性表皮生长因子受体（EGFR）抑制剂的设计，合成和生物学评估

对于具有EGFR激活突变的非小细胞肺癌（NSCLC）患者，第一代表皮生长因子受体（EGFR）抑制剂吉非替尼和厄洛替尼已初步获得了明显的临床疗效。然而，由于获得性抗药性突变的出现，其临床益处受到了限制。在大多数情况下（约60％），耐药性是由继发性EGFR T790M Gatekeeper突变引起的。因此，仍然需要开发新的第三代EGFR抑制剂以克服T790M突变，同时保留野生型（WT）EGFR。本文设计合成了一系列嘧啶并[4,5 - d ]嘧啶-2,4（1 H，3 H）-二酮衍生物，其中最有效的化合物20g不仅在体外对EGFR ^{L858R / T790M}和H1975细胞表现出显着的抑制活性和选择性，而且在H1975异种移植小鼠模型中显示出出色的抗肿瘤效率。在体外和体内水平上令人鼓舞的突变体选择性结果表明，20g可作为有效和选择性EGFR ^{L858R / T790M}抑制剂用作有前途的先导化合物，用于进一步的结构优化。