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Mol Oncol. 2019 Apr;13(4):946-958. doi: 10.1002/1878-0261.12454. Epub 2019 Feb 22.

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

Zhang B1,2, Wang L1,2,3, Zhang Q1, Yan Y1,2, Jiang H4, Hu R4, Zhou X5, Liu X5, Feng J6, Lin N1,2.

Author information

1
Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2
Affiliated Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
3
Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, China.
4
Department of Thoracic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
5
Hangzhou Hertz Pharmaceutical Co., China.
6
Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China.

Abstract

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.

KEYWORDS:

ABT-199; Ibr-7; ibrutinib; mTORC1, S6; non-small cell lung cancer

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