Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy , East China University of Science and Technology , Shanghai 200237 , China.
School of Pharmacy , Guizhou University of Chinese Medicine , Guiyang 550025 , China.
J Med Chem. 2018 Jul 12;61(13):5609-5622. doi: 10.1021/acs.jmedchem.8b00346. Epub 2018 Jun 25.
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(1 H,3 H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFR 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 inhibitors.
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为具有 EGFR 激活突变的非小细胞肺癌（NSCLC）患者取得了最初显著的临床疗效。然而，其临床获益受到获得性耐药突变的限制。在大多数情况下（约 60%），耐药性是由次要的 EGFR T790M 看门突变引起的。因此，仍然需要开发新型第三代 EGFR 抑制剂来克服 T790M 突变，同时保留野生型（WT）EGFR。在此，设计并合成了一系列嘧啶并[4,5-d]嘧啶-2,4(1H,3H)-二酮衍生物，其中最有效的化合物 20g 不仅在体外对 EGFR 和 H1975 细胞表现出显著的抑制活性和选择性，而且在 H1975 异种移植小鼠模型中也显示出优异的抗肿瘤功效。在体外和体内水平均取得令人鼓舞的突变选择性结果表明，20g 可能作为一种有前途的先导化合物，用于进一步作为有效的、选择性的 EGFR 抑制剂进行结构优化。
