HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4-de]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

中文翻译：

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发现针对野生型和 A775_G776insYVMA 突变 HER2 激酶的新型 5,6-二氢-4H-吡啶并[2,3,4-de]喹唑啉不可逆抑制剂

4% 的非小细胞肺癌 (NSCLC) 患者存在 HER2 突变。大多数突变 (90%) 作为外显子 20 框架内的插入突变发生，导致 PI3K-AKT 和 RAS/MAPK 通路的下游激活。然而，全球范围内尚未批准靶向治疗。这里设计并开发了一系列具有吡啶并[2,3,4-去]喹唑啉核心的高效 HER2 抑制剂。与阿法替尼和来那替尼相比，以吡啶并[2,3,4- de ]喹唑啉为核心的衍生物在具有 HER2insYVMA 突变的 BaF3 细胞中表现出更优异的抗增殖功效。大鼠研究表明，新开发核心的8a和9a具有良好的药代动力学特性，口服生物利用度分别为 41.7% 和 42.0%。口服4a和10e（30 mg/kg，QD）在体内异种移植模型中显示出显着的抗肿瘤功效。我们在本研究中提出了开发 HER2insYVMA 突变抑制剂的有前景的策略。