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The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling

Ibrutinib is a small molecule drug that targets Bruton's tyrosine kinase in B‐cell malignancies and is highly efficient at killing mantle cell lymphoma and chronic lymphocytic leukemia. However, the anti‐cancer activity of ibrutinib against solid tumors, such as non‐small cell lung cancer (NSCL...

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Autores principales: Zhang, Bo, Wang, Linling, Zhang, Qi, Yan, Youyou, Jiang, Hong, Hu, Runlei, Zhou, Xinglu, Liu, Xingguo, Feng, Jianguo, Lin, Nengming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441926/
https://www.ncbi.nlm.nih.gov/pubmed/30663221
http://dx.doi.org/10.1002/1878-0261.12454
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author Zhang, Bo
Wang, Linling
Zhang, Qi
Yan, Youyou
Jiang, Hong
Hu, Runlei
Zhou, Xinglu
Liu, Xingguo
Feng, Jianguo
Lin, Nengming
author_facet Zhang, Bo
Wang, Linling
Zhang, Qi
Yan, Youyou
Jiang, Hong
Hu, Runlei
Zhou, Xinglu
Liu, Xingguo
Feng, Jianguo
Lin, Nengming
author_sort Zhang, Bo
collection PubMed
description Ibrutinib is a small molecule drug that targets Bruton's tyrosine kinase in B‐cell malignancies and is highly efficient at killing mantle cell lymphoma and chronic lymphocytic leukemia. However, the anti‐cancer activity of ibrutinib against solid tumors, such as non‐small cell lung cancer (NSCLC), remains low. To improve the cytotoxicity of ibrutinib towards lung cancer, we synthesized a series of ibrutinib derivatives, of which Ibr‐7 exhibited superior anti‐cancer activity to ibrutinib, especially against epithelial growth factor receptor (EGFR) wild‐type NSCLC cell lines. Ibr‐7 was observed to dramatically suppress the mammalian target of Rapamycin complex 1 (mTORC1)/S6 signaling pathway, which is only slightly affected by ibrutinib, thus accounting for the superior anti‐cancer activity of Ibr‐7 towards NSCLC. Ibr‐7 was shown to overcome the elevation of Mcl‐1 caused by ABT‐199 mono‐treatment, and thus exhibited a significant synergistic effect when combined with ABT‐199. In conclusion, we used a molecular substitution method to generate a novel ibrutinib derivative, termed Ibr‐7, which exhibits enhanced anti‐cancer activity against NSCLC cells as compared with the parental compound.
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spelling pubmed-64419262019-04-11 The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling Zhang, Bo Wang, Linling Zhang, Qi Yan, Youyou Jiang, Hong Hu, Runlei Zhou, Xinglu Liu, Xingguo Feng, Jianguo Lin, Nengming Mol Oncol Research Articles Ibrutinib is a small molecule drug that targets Bruton's tyrosine kinase in B‐cell malignancies and is highly efficient at killing mantle cell lymphoma and chronic lymphocytic leukemia. However, the anti‐cancer activity of ibrutinib against solid tumors, such as non‐small cell lung cancer (NSCLC), remains low. To improve the cytotoxicity of ibrutinib towards lung cancer, we synthesized a series of ibrutinib derivatives, of which Ibr‐7 exhibited superior anti‐cancer activity to ibrutinib, especially against epithelial growth factor receptor (EGFR) wild‐type NSCLC cell lines. Ibr‐7 was observed to dramatically suppress the mammalian target of Rapamycin complex 1 (mTORC1)/S6 signaling pathway, which is only slightly affected by ibrutinib, thus accounting for the superior anti‐cancer activity of Ibr‐7 towards NSCLC. Ibr‐7 was shown to overcome the elevation of Mcl‐1 caused by ABT‐199 mono‐treatment, and thus exhibited a significant synergistic effect when combined with ABT‐199. In conclusion, we used a molecular substitution method to generate a novel ibrutinib derivative, termed Ibr‐7, which exhibits enhanced anti‐cancer activity against NSCLC cells as compared with the parental compound. John Wiley and Sons Inc. 2019-02-22 2019-04 /pmc/articles/PMC6441926/ /pubmed/30663221 http://dx.doi.org/10.1002/1878-0261.12454 Text en © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhang, Bo
Wang, Linling
Zhang, Qi
Yan, Youyou
Jiang, Hong
Hu, Runlei
Zhou, Xinglu
Liu, Xingguo
Feng, Jianguo
Lin, Nengming
The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling
title The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling
title_full The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling
title_fullStr The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling
title_full_unstemmed The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling
title_short The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling
title_sort ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mtorc1/s6 signaling
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441926/
https://www.ncbi.nlm.nih.gov/pubmed/30663221
http://dx.doi.org/10.1002/1878-0261.12454
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