[HTML][HTML] Discovery of a series of 1, 2, 3-triazole-containing erlotinib derivatives with potent anti-tumor activities against non-small cell lung cancer
G Sun, L Mao, W Deng, S Xu, J Zhao, J Yang… - Frontiers in …, 2022 - frontiersin.org
G Sun, L Mao, W Deng, S Xu, J Zhao, J Yang, K Yao, M Yuan, W Li
Frontiers in Chemistry, 2022•frontiersin.orgEpidermal 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 …
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 …
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.
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