DataSheet12_Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer.zip

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are emerging at the vanguard of therapy for non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the increasing therapeutic resistance caused by novel mutations or activated bypass pathways has impaired their performance. In this study, we link one of the commercial EGFR-TKIs, Erlotinib, to different azide compounds to synthesize a novel class of 1,2,3-triazole ring-containing Erlotinib derivatives. We discovered that several new compounds show robust antiproliferation activity against diverse NSCLC cells in vitro including PC-9, H460, H1975 and A549. Two of the most potent compounds, e4 and e12 have been found to be more efficient than Erlotinib in all NSCLC cell lines except PC-9. They significantly induce apoptosis and cell cycle arrest in PC-9 and H460 cells. The antitumor efficacy of compound e4 in vivo is close to that of Erlotinib in a PC-9 xenograft mouse model. Most Erlotinib-1,2,3-triazole compounds exhibit moderate to good inhibitory activities toward wild-type EGFR as indicated by enzyme-linked immunosorbent assay (ELISA), and the EGFR phosphorylation was inhibited in H460 and PC-9 cells exposed to e4 or e12. These data suggest that these Erlotinib-1,2,3-triazole compounds are suitable candidates for use against NSCLC and more unknown mechanisms merit further investigation.

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）已成为携带EGFR激活突变的非小细胞肺癌（NSCLC）患者治疗的前沿方案。然而，由新型突变或激活的旁路通路引发的治疗耐药性不断增加，削弱了其临床疗效。本研究将商用EGFR-TKI之一厄洛替尼与不同叠氮化合物结合，合成了一类新型的含1,2,3-三唑环的厄洛替尼衍生物。研究发现，多款新型化合物在体外对包括PC-9、H460、H1975及A549在内的多种非小细胞肺癌细胞均表现出强劲的抗增殖活性。其中两款活性最强的化合物e4与e12，在除PC-9外的所有非小细胞肺癌细胞系中的作用效果均优于厄洛替尼。它们可显著诱导PC-9与H460细胞发生凋亡及细胞周期阻滞。在PC-9异种移植小鼠模型中，化合物e4的体内抗肿瘤疗效与厄洛替尼相当。酶联免疫吸附测定（ELISA）结果显示，多数厄洛替尼-1,2,3-三唑类化合物对野生型EGFR具有中等至良好的抑制活性，而用e4或e12处理H460与PC-9细胞后，其EGFR磷酸化水平受到抑制。上述研究结果表明，这类厄洛替尼-1,2,3-三唑类化合物可作为抗非小细胞肺癌的候选药物，其更多未知的作用机制有待进一步探究。