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However, the anti\u2010cancer activity of ibrutinib against solid tumors, such as non\u2010small cell lung cancer (<jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content>), remains low. To improve the cytotoxicity of ibrutinib towards lung cancer, we synthesized a series of ibrutinib derivatives, of which Ibr\u20107 exhibited superior anti\u2010cancer activity to ibrutinib, especially against epithelial growth factor receptor (<jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content>) wild\u2010type <jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content> cell lines. Ibr\u20107 was observed to dramatically suppress the mammalian target of Rapamycin complex 1 (<jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1)\/S6 signaling pathway, which is only slightly affected by ibrutinib, thus accounting for the superior anti\u2010cancer activity of Ibr\u20107 towards <jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content>. Ibr\u20107 was shown to overcome the elevation of Mcl\u20101 caused by <jats:styled-content style=\"fixed-case\">ABT<\/jats:styled-content>\u2010199 mono\u2010treatment, and thus exhibited a significant synergistic effect when combined with <jats:styled-content style=\"fixed-case\">ABT<\/jats:styled-content>\u2010199. In conclusion, we used a molecular substitution method to generate a novel ibrutinib derivative, termed Ibr\u20107, which exhibits enhanced anti\u2010cancer activity against <jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content> cells as compared with the parental compound.<\/jats:p>","DOI":"10.1002\/1878-0261.12454","type":"journal-article","created":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T07:15:09Z","timestamp":1548054909000},"page":"946-958","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Ibr\u20107 derivative of ibrutinib exhibits enhanced cytotoxicity against non\u2010small cell lung cancer cells via targeting of <scp>mTORC<\/scp>1\/S6 signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Bo","family":"Zhang","sequence":"first","affiliation":[{"name":"Translational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China"},{"name":"Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linling","family":"Wang","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China"},{"name":"Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China"},{"name":"Shaoxing Hospital of Traditional Chinese Medicine Shaoxing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youyou","family":"Yan","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Center Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China"},{"name":"Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runlei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinglu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hangzhou Hertz Pharmaceutical Co. 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