Send to

Choose Destination
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

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


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.


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

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center