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

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...

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Autores principales: Sun, Ge, Mao, Longfei, Deng, Wenjing, Xu, Shuxiang, Zhao, Jie, Yang, Jianxue, Yao, Kaitai, Yuan, Miaomiao, Li, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776995/
https://www.ncbi.nlm.nih.gov/pubmed/35071184
http://dx.doi.org/10.3389/fchem.2021.789030
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author Sun, Ge
Mao, Longfei
Deng, Wenjing
Xu, Shuxiang
Zhao, Jie
Yang, Jianxue
Yao, Kaitai
Yuan, Miaomiao
Li, Wei
author_facet Sun, Ge
Mao, Longfei
Deng, Wenjing
Xu, Shuxiang
Zhao, Jie
Yang, Jianxue
Yao, Kaitai
Yuan, Miaomiao
Li, Wei
author_sort Sun, Ge
collection PubMed
description 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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spelling pubmed-87769952022-01-22 Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer Sun, Ge Mao, Longfei Deng, Wenjing Xu, Shuxiang Zhao, Jie Yang, Jianxue Yao, Kaitai Yuan, Miaomiao Li, Wei Front Chem Chemistry 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. Frontiers Media S.A. 2022-01-07 /pmc/articles/PMC8776995/ /pubmed/35071184 http://dx.doi.org/10.3389/fchem.2021.789030 Text en Copyright © 2022 Sun, Mao, Deng, Xu, Zhao, Yang, Yao, Yuan and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Sun, Ge
Mao, Longfei
Deng, Wenjing
Xu, Shuxiang
Zhao, Jie
Yang, Jianxue
Yao, Kaitai
Yuan, Miaomiao
Li, Wei
Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer
title Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer
title_full Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer
title_fullStr Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer
title_full_unstemmed Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer
title_short Discovery of a Series of 1,2,3-Triazole-Containing Erlotinib Derivatives With Potent Anti-Tumor Activities Against Non-Small Cell Lung Cancer
title_sort discovery of a series of 1,2,3-triazole-containing erlotinib derivatives with potent anti-tumor activities against non-small cell lung cancer
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776995/
https://www.ncbi.nlm.nih.gov/pubmed/35071184
http://dx.doi.org/10.3389/fchem.2021.789030
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