Lung cancer is the most common cancer and leading cause of cancer-related deaths worldwide. The first-generation reversible, ATP-competitive inhibitors gefetinib and elotinib showed good clinical responses in lung adenocarcinoma tumors (NSCLC). But almost all patients developed resistance to these inhibitors over time. Such resistance of EGFR inhibitors was frequently linked to the acquired L858R and T790M point mutations in the kinase domain of EGFR. To overcome these resistance problems, the second and the third generation inhibitors have been discovered. FDA approved afatinib, the second generation irreversible inhibitor and osimitinib, the third generation irreversible EGFR inhibitors for the treatments of NSCLC. We identified new covalent quinazoline inhibitors (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (6d) and (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethyl-amino)but-2-enamide (6h) that exhibited potent EGFR kinase inhibitory activities on L858R and T790M mutations. The compound 6 h showed selectivity similar to AZD9291 (osimertinib) in mutated and wild type tumor cell lines. In vitro cell assay 6d and 6h were better than afatinib and osimertinib. In vivo antitumor efficacy studies of these compounds were done in NCI-H1975 mice xenografts.

中文翻译：

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新型喹唑啉衍生物作为不可逆的双重EGFR / HER2抑制剂在肺癌异种移植（NCI-H1975）小鼠模型中的体内功效研究。

肺癌是全球最常见的癌症，也是与癌症相关的死亡的主要原因。第一代可逆的，具有ATP竞争性的抑制剂吉非替尼和埃洛替尼在肺腺癌肿瘤（NSCLC）中表现出良好的临床反应。但是随着时间的流逝，几乎所有患者对这些抑制剂都产生了耐药性。EGFR抑制剂的这种耐药性通常与EGFR激酶域中的获得性L858R和T790M点突变相关。为了克服这些抗性问题，已经发现了第二代和第三代抑制剂。FDA批准第二代不可逆抑制剂afatinib和第三代不可逆EGFR抑制剂osimitinib用于NSCLC的治疗。我们确定了新的共价喹唑啉抑制剂（E）-N-（4-（3-氯-4-氟苯基氨基）-7-（2-乙氧基乙氧基）喹唑啉-6-基）-4-（二甲基氨基）丁-2-烯酰胺（ 6d）和（E）-N-（4-（3-氯-4-（吡啶-2-基甲氧基）苯基氨基）-7-（2-乙氧基乙氧基）喹唑啉-6-基）-4-（二甲基氨基）但对L858R和T790M突变表现出有效的EGFR激酶抑制活性的2--2-酰胺（6h）。化合物6 h在突变和野生型肿瘤细胞系中显示出与AZD9291（osimertinib）相似的选择性。体外细胞试验6d和6h优于afatinib和osimertinib。在NCI-H1975小鼠异种移植物中进行了这些化合物的体内抗肿瘤功效研究。