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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doaj-e5c3d1335dc445a0871f4cc0c2c3efd62020-11-25T03:54:59ZengWileyMolecular Oncology1574-78911878-02612019-04-0113494695810.1002/1878-0261.12454The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signalingBo Zhang0Linling Wang1Qi Zhang2Youyou Yan3Hong Jiang4Runlei Hu5Xinglu Zhou6Xingguo Liu7Jianguo Feng8Nengming Lin9Translational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaTranslational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaTranslational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaTranslational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Thoracic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaDepartment of Thoracic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaHangzhou Hertz Pharmaceutical Co. ChinaHangzhou Hertz Pharmaceutical Co. ChinaCancer Research Institute Zhejiang Cancer Hospital Hangzhou ChinaTranslational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou ChinaIbrutinib 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.https://doi.org/10.1002/1878-0261.12454ABT‐199Ibr‐7ibrutinibmTORC1, S6non‐small cell lung cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bo Zhang Linling Wang Qi Zhang Youyou Yan Hong Jiang Runlei Hu Xinglu Zhou Xingguo Liu Jianguo Feng Nengming Lin |
spellingShingle |
Bo Zhang Linling Wang Qi Zhang Youyou Yan Hong Jiang Runlei Hu Xinglu Zhou Xingguo Liu Jianguo Feng Nengming Lin The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling Molecular Oncology ABT‐199 Ibr‐7 ibrutinib mTORC1, S6 non‐small cell lung cancer |
author_facet |
Bo Zhang Linling Wang Qi Zhang Youyou Yan Hong Jiang Runlei Hu Xinglu Zhou Xingguo Liu Jianguo Feng Nengming Lin |
author_sort |
Bo Zhang |
title |
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_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_sort |
ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mtorc1/s6 signaling |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2019-04-01 |
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. |
topic |
ABT‐199 Ibr‐7 ibrutinib mTORC1, S6 non‐small cell lung cancer |
url |
https://doi.org/10.1002/1878-0261.12454 |
work_keys_str_mv |
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