表皮生长因子受体酪氨酸激酶抑制剂 (EGFR TKI) 已被证明能够通过抑制 EGFR 表达来阻止肿瘤细胞增殖。尽管如此，接受治疗的患者可能会获得耐药性，这种耐药性可能通过EGFR依赖性（如T790M突变）或EGFR非依赖性（如c-Met扩增）方式发生。因此，开发双靶点抑制剂可能为解决患者治疗获得性耐药提供潜在途径。在此，我们设计、合成和筛选了几种新型4-苯氧基喹唑啉衍生物，旨在寻找一种有效的EGFR/c-Met双重抑制剂用于治疗NSCLC，其中H-22成为最有前途的候选药物，具有显着的抗肿瘤特性。此外，我们评估了 H-22 对五种癌细胞系中 EGFR 激酶和 c-Met 激酶的体外抑制作用。此外，还进行了一系列功能实验（细胞周期、凋亡测定、体外/体内动物模型等），以进一步研究H-22的抗肿瘤机制。目前的研究表明，H-22 在体外和体内均表现出很强的抗肿瘤活性。有趣的是，H-22 对所有五种癌细胞表现出与阿法替尼相似的抗增殖活性 (2.27-3.35 μM)，在浓度为 64.8、305.4 和 137.4 nM 时对 EGFRWT、EGFRL858R/T790M 和 c-Met 激酶具有抑制功能， 分别。细胞周期分析表明，H-22 的抗增殖活性与其引起 G2/M 期停滞的能力相关。此外，体内数据表明，H-22 可以抑制我们的异种移植模型中的肿瘤生长并诱导细胞凋亡。总的来说，我们的研究发现 H-22 是一种新型 EGFR 和 c-Met 双重抑制剂，也是一种前瞻性抗肿瘤治疗药物。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have demonstrated the ability to impede tumor cell proliferation by suppressing EGFR expression. Nonetheless, patients undergoing treatment may acquire resistance, which may occur through an EGFR-dependent (such as T790M mutation) or an EGFR-independent (such as c-Met amplification) manner. Therefore, developing dual-target inhibitors might present a potential avenue for addressing treatment-acquired resistance in patients. Herein, we designed, synthesized, and screened several novel 4-phenoxyquinazoline derivatives, aiming to identify a potent dual EGFR/c-Met inhibitor for the treatment of NSCLC, among which H-22 emerged as the most promising candidate exhibiting significant antitumor properties. Moreover, we assessed the in vitro inhibitory effect of H-22 on EGFR kinase and c-Met kinase in five cancer cell lines. In addition, a series of functional experiments (cell cycle, apoptosis assays, in vitro/in vivo animal model, etc.) were conducted to further investigate the anti-tumor mechanisms of H-22. The present study revealed that H-22 exhibited strong antitumor activity both in vitro and in vivo. Interestingly, H-22 exhibited anti-proliferative activity (2.27-3.35 μM) similar to Afatinib against all five cancer cells, with inhibitory functions against EGFRWT, EGFRL858R/T790M, and c-Met kinases at a concentration of 64.8, 305.4 and 137.4 nM, respectively. Cell cycle analysis indicated that the antiproliferative activity of H-22 was associated with its ability to cause G2/M arrest. Furthermore, in vivo data showed that H-22 could inhibit tumor growth in our xenograft models and induce apoptosis. Collectively, our findings uncovered that H-22 is a novel dual EGFR and c-Met inhibitor and a prospective anti-tumor therapeutic drug.Copyright © 2023 Elsevier Inc. All rights reserved.