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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Autoantigens / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Caspases / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • ErbB Receptors / genetics
  • Female
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice, Nude
  • Mutation / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Phosphorylation / drug effects
  • Piperidines
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Ribonucleoproteins / metabolism
  • Ribosomal Protein S6 / metabolism*
  • SS-B Antigen
  • Signal Transduction* / drug effects
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Autoantigens
  • Bridged Bicyclo Compounds, Heterocyclic
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Piperidines
  • Pyrazoles
  • Pyrimidines
  • Ribonucleoproteins
  • Ribosomal Protein S6
  • Sulfonamides
  • ibrutinib
  • ErbB Receptors
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Caspases
  • Adenine
  • venetoclax