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Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer
Biomaterials Science ( IF 6.6 ) Pub Date : 2020-03-26 , DOI: 10.1039/d0bm00293c
Lili Yang 1 , Shanshan Liu , Jingjing Chu , Shuang Miao , Kai Wang , Qingwei Zhang , Yingyi Wang , Yadi Xiao , Lina Wu , Yang Liu , Longjian Yu , Caihong Yu , Xiang Liu , Mingxing Ke , Zhen Cheng , Xilin Sun
Affiliation  

The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). EGFR-TKI positron emission tomography (PET) probes based on the central quinazoline core show great potential for NSCLC diagnosis, and pre-clinical and clinical therapy monitoring. In our previous research, anilino quinazoline based PET probe, N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18F-MPG), have been developed, and it has been successfully demonstrated to be a powerful non-invasive imaging tool for differentiating EGFR mutation status and stratifying NSCLC patients for EGFR-TKI treatment in a clinical study (n = 75 patients). Moreover, it has been found that 18F-MPG shows excellent tumor targeting performance and good pharmacokinetic characteristics in NSCLC patients. These results motivate us to investigate the cancer treatment efficacy of non-radioactive F-MPG and its analogue N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-hydroxyethoxy)ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (OH-MPG) in vitro and in small animal models. Our studies revealed that both F-MPG and OH-MPG displayed high therapeutic effect to NSCLC cells (IC50 = 5.3 nM and 2.0 nM to HCC827 cells for F-MPG and OH-MPG, respectively). More importantly, compared with a standard EGFR-TKI, 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD153035), F-MPG and OH-MPG showed stronger tumor inhibition in preclinical models. Furthermore, the treatment efficacy of F-MPG or OH-MPG monitored by 18F-FDG-PET indicated that tumor uptake in treated groups was significantly decreased. Ex vivo experiments showed that the levels of serum biomarkers and pathological changes in the liver were significantly reduced in the F-MPG and OH-MPG group, compared to PD153035 treated group. In conclusion, EGFR targeted F-MPG and OH-MPG exhibit promising anti-tumor activity with limited liver damage, thus representing promising drug candidates for further investigation for combating the deadly NSCLC.

中文翻译:

基于苯胺基喹唑啉的新型 EGFR 酪氨酸激酶抑制剂用于治疗非小细胞肺癌

表皮生长因子受体 (EGFR)-酪氨酸激酶抑制剂 (TKI) 彻底改变了非小细胞肺癌 (NSCLC) 的治疗。基于中心喹唑啉核心的 EGFR-TKI 正电子发射断层扫描 (PET) 探针在 NSCLC 诊断、临床前和临床治疗监测方面显示出巨大潜力。在我们之前的研究中,基于苯胺基喹唑啉的 PET 探针,N- (3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2- 18 F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6 -methoxyquinazolin-4-amine ( 18 F-MPG) 已被开发出来,并已在临床研究中成功证明是一种强大的非侵入性成像工具,用于区分 EGF​​R 突变状态和对 NSCLC 患者进行 EGFR-TKI 治疗进行分层( n= 75 名患者)。此外,已发现18 F-MPG 在 NSCLC 患者中表现出优异的肿瘤靶向性能和良好的药代动力学特征。这些结果促使我们研究非放射性 F-MPG 及其类似物N- (3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-hydroxyethoxy)ethoxy))的癌症治疗效果ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (OH-MPG)在体外和小动物模型中。我们的研究表明,F-MPG 和 OH-MPG 对 NSCLC 细胞均表现出较高的治疗效果(IC 50对于 F-MPG 和 OH-MPG,HCC827 细胞分别 = 5.3 nM 和 2.0 nM)。更重要的是,与标准 EGFR-TKI 相比,4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD153035)、F-MPG 和 OH-MPG 在临床前模型中表现出更强的肿瘤抑制作用。此外,通过18 F-FDG-PET监测的 F-MPG 或 OH-MPG 的治疗效果表明,治疗组的肿瘤摄取显着降低。离体实验表明,与 PD153035 治疗组相比,F-MPG 和 OH-MPG 组的血清生物标志物水平和肝脏病理变化显着降低。总之,EGFR 靶向 F-MPG 和 OH-MPG 表现出有希望的抗肿瘤活性,且肝损伤有限,因此代表了有希望的候选药物,可用于进一步研究对抗致命的 NSCLC。
更新日期:2020-04-24
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