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.
Mol Oncol. 2019 Apr;13(4):946-958. doi: 10.1002/1878-0261.12454. Epub 2019 Feb 22.
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.
伊布替尼是一种小分子药物，靶向 B 细胞恶性肿瘤中的布鲁顿酪氨酸激酶，对套细胞淋巴瘤和慢性淋巴细胞白血病具有高效的杀伤作用。然而，伊布替尼对实体瘤（如非小细胞肺癌（NSCLC））的抗癌活性仍然较低。为了提高伊布替尼对肺癌的细胞毒性，我们合成了一系列伊布替尼衍生物，其中伊布-7对伊布替尼表现出优越的抗癌活性，特别是对表皮生长因子受体（EGFR）野生型 NSCLC 细胞系。伊布-7 显著抑制雷帕霉素复合物 1（mTORC1）/S6 信号通路，而伊布替尼对该通路的影响较小，这也是伊布-7 对 NSCLC 具有优越抗癌活性的原因。伊布-7 能够克服 ABT-199 单药治疗引起的 Mcl-1 升高，因此与 ABT-199 联合使用时具有显著的协同作用。总之，我们使用分子取代方法生成了一种新型伊布替尼衍生物，称为伊布-7，与母体化合物相比，它对 NSCLC 细胞表现出增强的抗癌活性。
